ES2454966T3 - Compounds for the prevention and treatment of cardiovascular diseases - Google Patents

Abstract

Compound of formula II for use to increase the expression of ApoA-I in a mammal: ** Formula ** in which: X is N; R1 and R3 are each independently selected from alkoxy and hydrogen; R2 is selected from alkoxy, alkyl and hydrogen; R6 and R8 are each independently selected from alkyl, alkoxy, chloride and hydrogen; R4 and R5 are hydrogen; R7 is selected from amino, hydroxyl, alkoxy and alkyl substituted with a heterocyclyl, or two adjacent substituents selected from R6, R7 and R8 are connected to form a heterocyclyl; each W is independently selected from C and N; p is 1, with the exception that when W is N, then p is 0; wherein the "alkyl", "alkenyl", "alkynyl", "alkoxy", "amino" and "amide" groups may be substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulphide, sulfinyl, sulfonyl, sulfonic acid , sulfonamide, thioketone, ureido and N; with the proviso that if R2 is selected from alkoxy or hydrogen, then at least one of R1 and R3 is alkoxy; with the proviso that if R7 is selected from hydroxyl or alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy and chloride; with the proviso that if for W- (R7) p, W is N and p is 0, then at least one of R6 and R8 is chloride; and pharmaceutically acceptable salts and hydrates thereof.

Description

Compounds for the prevention and treatment of cardiovascular diseases

Technical field

The present disclosure relates to compounds, which are useful for regulating the expression of apolipoprotein AI (ApoA-I), and their use for the treatment and prevention of cardiovascular disease and related pathological conditions, including cholesterol or lipid-related disorders, such as, for example, atherosclerosis.

Background

Epidemiological data demonstrate an inverse relationship between circulating levels of high-density lipoprotein cholesterol (C-HDL) and the incidence of clinically significant atherosclerosis. Each 1 mg / dL increase in serum C-HDL level is associated with a 2-3% decrease in cardiovascular risk; a 1% reduction in LDL-C reduces the risk of coronary heart disease (CHD) by 2% (Gordon et al. (1997) Am. J. Med. 62, 707-714). Experimental tests further support the protective effect of C-HDL against cardiovascular disease. For example, in subjects with low C-HDL, the administration of gemfibrozil results in a 6% increase in the level of C-HDL and a corresponding 22% reduction in the risk of CHD (Rubins et al. (1999) N Engl. J. Med. 341, 410-418). Observations in genetic disorders associated with low C-HDL due to reduced ApoA-I expression also indicate a link between high risk of CHD and low C-HDL.

C-HDL seems to exert its antiatetrogenic effect by mediating the transport of reverse cholesterol (RCT), in which cholesterol is collected from peripheral tissues and transported to the liver. In addition, C-HDL also exerts anti-inflammatory and antioxidant effects and promotes fibrinolysis. C-HDL particles protect against the oxidation of LDL, an important initial stage in the promotion of cholesterol uptake by arterial macrophages. C-HDL exists in two main forms, containing both apolipoprotein AI (ApoA-I) and apolipoprotein A-II (ApoA-II), and containing the other ApoA-I without ApoA-II (Schultz et al. (1993) Nature 365, 762-764). The cardioprotective effect of C-HDL is attributed mainly, but not exclusively, to ApoA-I.

Clinical and experimental data suggest that the production of ApoA-I is a critical determinant of circulating C-HDL. For example, it seems that people with familial hyperalphalipoproteinemia (high ApoA-I) are protected against atherosclerosis, while those deficient in ApoA-I (hypoalphalipoproteinemia) show accelerated cardiovascular disease. In addition, various experimental manipulations to increase the production of ApoA-I are associated with a reduced atherogenicity. For example, human ApoA-I is protective in transgenic animal models (Shah et al. (1998) Circulation 97, 780-785; Rubin et al. (1991) Nature 353, 265-267), and treatment with ApoA -Imilane prevents atherosclerotic lesions and leads to regression of atherosclerotic plaques in human patients (Nissen et al. (2003) JAMA 290, 2292-2300). Additional lines of research show that ApoA-I plays a role in enhancing the transport of reverse cholesterol, reducing oxidative stress, increasing paraoxonase activity, enhancing anticoagulant activity and increasing anti-inflammatory activity (Andersson (1997) Curr. Opin. Lipidol .8, 225-228). Therefore, ApoA-I is an attractive target for therapeutic intervention.

Currently available therapeutic agents that increase the plasma concentration of ApoA-I, for example, recombinant ApoA-I or peptides that mimic ApoA-I, have potential drawbacks with respect to, for example, storage stability, administration of active product and half-life in vivo. Therefore, small molecule compounds that regulate by increasing the production of endogenous ApoA-I, such as, for example, regulators by increasing the expression of ApoA-I, would be very attractive as new therapeutic agents for cardiovascular disease. Such small molecule compounds have been described in WO 2006/045038.

The compounds of the present invention represent a significant improvement over the compounds disclosed in WO 2006/045096. Specifically, the compounds of the present invention are more potent in more than one order of magnitude than the more active compounds described in that publication, such as 2- (4-hydroxy-phenyl) -pyran [2,3-b] pyridine- 4-one

2- (4-hydroxy-phenyl) -pyran [2,3-b] pyridin-4-one

Summary

The present invention includes compounds that are not produced naturally that are useful for regulating the expression of apolipoprotein AI (ApoA-I), and its use in the treatment and prevention of cardiovascular disease and related pathological conditions, including cholesterol-related disorders and with lipids, such as, for example, atherosclerosis.

The invention includes a compound of formula II for use to increase the expression of ApoA-I in a mammal:

10 Formula II in which: X is N; R1 and R3 are each independently selected from alkoxy and hydrogen; R2 is selected from alkoxy, alkyl and hydrogen;

R6 and R8 are each independently selected from alkyl, alkoxy, chloride and hydrogen; R4 and R5 are hydrogen; R7 is selected from amino, hydroxyl, alkoxy and alkyl substituted with a heterocyclyl, or two adjacent substituents selected from R6, R7 and R8 are connected to form a heterocyclyl;

20 each W is independently selected from C and N; p is 1, with the exception that when W is N, then p is 0; wherein the groups "alkyl", "alkenyl", "alkynyl", "alkoxy", "amino" and "amide" may be substituted with or

interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido and N;

with the proviso that if R2 is selected from alkoxy or hydrogen, then at least one of R1 and R3 is alkoxy; with the proviso that if R7 is selected from hydroxyl or alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy and chloride;

with the proviso that if for W- (R7) p, W is N and p is 0, then at least one of R6 and R8 is chloride; and pharmaceutically acceptable salts and hydrates thereof. In some embodiments of the invention, R7 is an amino or alkoxy group selected from the group represented by

Formula III:

5 Formula III in which: A is selected from O and N; n is selected from 0, 1, 2, 3, 4 and 5; 10 B is selected from -C (O) N (Rh) 2-, -S (O) 2N (Rh) 2-, -C (O) -, -S (O) 2-, -C (O) O -, wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen; and R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen. In another embodiment, if A is O and B is -C (O) NH-, then R20 is not an unsaturated cycloalkyl group. The invention also includes a compound of formula II:

Formula II in which:

20 X is N; R1 and R3 are each independently selected from alkoxy and hydrogen; R2 is selected from alkoxy, alkyl and hydrogen; R6 and R8 are each independently selected from alkyl, alkoxy, chloride and hydrogen; R4 and R5 are hydrogen;

R7 is selected from amino, hydroxyl, alkoxy and alkyl substituted with a heterocyclyl; or two adjacent substituents selected from R6, R7 and R8 are connected to form a heterocyclyl; each W is independently selected from C and N; p is 1, with the exception that when W is N, then p is 0;

With the proviso that if R2 is selected from alkoxy or hydrogen, then at least one of R1 and R3 is alkoxy; with the proviso that if R7 is selected from hydroxyl or alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy and chloride;

with the proviso that if for W- (R7) p, W is N and p is 0, then at least one of R6 and R8 is chloride;

and pharmaceutically acceptable salts and hydrates thereof.

In certain embodiments, the compounds and compositions of the invention are useful for the prevention or treatment of diseases that benefit from elevated ApoA-I or HDL, and diseases characterized by reduced ApoA-I and / or C-HDL, lipid parameters abnormal or lipid parameters that indicate high cholesterol. The compounds and compositions of the invention can be used to increase the expression of ApoA-I. Increasing the expression of ApoA-I may refer to, but is not limited to, transcriptionally modulating the expression of the ApoA-I gene, thus affecting the level of the ApoA-I protein produced (synthesized and secreted). An increase in ApoA-I levels can lead to an increase in C-HDL levels and / or an increase in the functionality of C-HDL particles. Therefore, the compounds and compositions of the invention can also be used to reduce cholesterol levels. Accordingly, the methods, compounds and compositions of the invention can be used for the treatment and prevention of cardiovascular disease and related pathological conditions, particularly cholesterol or lipid related disorders, such as, for example, atherosclerosis.

Brief description of the figures

Figure 1 depicts the plasma levels of ApoA-I in hApoA-I transgenic mice that received 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 7 ) (10, 30 and 60 mg / kg body weight) twice a day for 7 days by oral tube.

Figure 2 depicts plasma levels of HDL cholesterol in hApoA-I transgenic mice that received 2 (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 7 ) (10 and 30 mg / kg body weight) twice daily for 7 days by oral tube.

Figure 3 depicts the plasma levels of ApoA-I in wild C57BL / 6 mice that received 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 7 ) (10, 30 and 60 mg / kg body weight) twice daily for 3 days by intraperitoneal administration.

Figure 4 depicts plasma HDL cholesterol levels in wild C57 / BI mice that received 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 7) (10, 30 and 60 mg / kg body weight) twice a day for 3 days by oral tube.

Figure 5 depicts the plasma levels of ApoA-I and tissue levels of ApoA-I mRNA in hApoA-I transgenic mice that were administered 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) - 5,7-dimethoxyquinazolin-4 (3H) one (example 7) (30 mg / kg body weight) twice daily for 7 days by oral tube.

Detailed description

Definitions

The term "aldehyde" or "formyl" as used herein refers to -CHO.

The term "alkenyl" as used herein refers to a linear or branched unsaturated hydrocarbon having at least one carbon-carbon double bond, such as a linear or branched group of 2-22, 2-8 or 2 -6 carbon atoms, referred to herein as alkenyl (C2-C22), alkenyl (C2-C8) and alkenyl (C2-C6), respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4- (2-methyl- 3-butene) pentenyl, etc.

The term "alkoxy" as used herein refers to an alkyl group attached to an oxygen (-Oalkyl-). The "alkoxy" groups also include an alkenyl group attached to an oxygen ("alkenyloxy") or an alkynyl group attached to an oxygen ("alkynyloxy"). Exemplary alkoxy groups include, but are not limited to, groups with an alkyl, alkenyl or alkynyl group of 1-22, 1-8 or 1-6 carbon atoms, referred to herein as (C1-C22 alkoxy) ), (C1-C8) alkoxy and (C1-C6) alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, etc.

The term "alkyl" as used herein refers to a linear or branched saturated hydrocarbon, such as a linear or branched group of 1-22, 1-8 or 1-6 carbon atoms, referred to herein. document (C1-C22) alkyl, (C1-C8) alkyl and (C1-C6) alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2pentyl , 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, butyl , pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

The term "alkynyl" as used herein refers to a linear or branched unsaturated hydrocarbon having at least one carbon-carbon triple bond, such as a linear or branched group of 2-22, 2-8 or 2 -6 carbon atoms, referred to herein as alkynyl (C2-C22), alkynyl (C2-C8) and alkynyl (C2-C6), respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentinyl, hexinyl, methylpropyl, 4-methyl-1-butynyl, 4-propyl-2-pentinyl and 4-butyl-2-hexinyl , etc.

The term "amide" as used herein refers to the form -NRaC (O) (Rb) - or -C (O) NRbRc, in which Ra, Rb and Rc are each independently selected from alkyl , alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen. The amide can bind to another group through carbon, nitrogen, Rb or Rc. The amide can also be cyclic, for example Rb and Rc, can be joined to form a 3 to 12 member ring, such as a 3 to 10 member ring or a 5 to 6 member ring. The term "amide" encompasses groups such as sulfonamide, urea, ureido, carbamate, carbamic acid, and cyclic versions thereof. The term "amide" also encompasses an amide group attached to a carboxyl group, for example, -amide-COOH or salts such as -amide-COONa, etc., an amino group attached to a carboxyl group, for example, -amino- COOH or salts such as -amino-COONa, etc.

The term "amine" or "amino" as used herein refers to the form -NRdRe or -N (Rd) Re-, in which Rd and Re are independently selected from alkyl, alkenyl, alkynyl, aryl , arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen. The amino group may be attached to the original molecular group through nitrogen. The amino group can also be cyclic, for example any two of Rd and Re can be joined together or with the N to form a 3- to 12-membered ring, for example, morpholino or piperidinyl. The term amino also includes the corresponding quaternary ammonium salt of any amino group. Exemplary amino groups include alkylamino groups, in which at least one of Rd or Re is an alkyl group.

The term "aryl" as used herein refers to a mono, bi or other multicarbocyclic aromatic ring system. The aryl group may optionally be condensed to one or more rings selected from aryl, cycloalkyl and heterocyclyl groups. The aryl groups of this invention may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl , heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulphide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl, as well as benzo condensed carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to a monocyclic aromatic ring system, in which the ring comprises 6 carbon atoms, referred to herein as "aryl (C6)".

The term "arylalkyl" as used herein refers to an alkyl group having at least one aryl substituent, for example -aryl-alkyl-. Exemplary arylalkyl groups include, but are not limited to, arylalkyl groups having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "aryl (C5) alkyl".

The term "aryloxy" as used herein refers to an aryl group attached to an oxygen atom. Exemplary aryloxy groups include, but are not limited to, aryloxy groups having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "C6) aryloxy."

The term "arylthio" as used herein refers to an aryl group attached to a sulfur atom. Exemplary arylthio groups include, but are not limited to, arylthio groups having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "arylthio (C6)".

The term "arylsulfonyl" as used herein refers to an aryl group attached to a sulfonyl group, for example, -S (O) 2-aryl-. Exemplary arylsulfonyl groups include, but are not limited to, arylsulfonyl groups having a monocyclic aromatic ring system, wherein the ring comprises 6 carbon atoms, referred to herein as "C6) arylsulfonyl."

The term "benzyl" as used herein refers to the group -CH2-phenyl.

The term "bicyclic aryl" as used herein refers to an aryl group fused to another aromatic or non-aromatic carbocyclic or heterocyclic ring. Exemplary bicyclic aryl groups include, but are not limited to, naphthyl or partially reduced forms thereof, such as di, tetra or hexahydronaphthyl.

The term "bicyclic heteroaryl" as used herein refers to a heteroaryl group fused to another aromatic or non-aromatic carbocyclic or heterocyclic ring. Exemplary bicyclic heteroaryl groups include, but are not limited to, systems condensed in 5.6 or 6.6 in which one or both rings contain heteroatoms. The term "bicyclic heteroaryl" also encompasses reduced or partially reduced forms of the condensed aromatic system in which one or both rings contain ring heteroatoms. The ring system can contain up to three heteroatoms, independently selected from oxygen, nitrogen or sulfur. The bicyclic system may be optionally substituted with one or more groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Exemplary bicyclic heteroaryl groups include, but are not limited to, quinazolinyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridinyl.

The term "carbamate" as used herein refers to the form -RgOC (O) N (Rh) -, -RgOC (O) N (Rh) Ri- or -OC (O) NRhRi, in that Rg, Rh and Ri are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydrogen. Exemplary carbamates include, but are not limited to, arylcarbamates or heteroarylcarbamates, for example, in which at least one of Rg, Rh and Ri is independently selected from aryl or heteroaryl, such as pyridine, pyridazine, pyrimidine and pyrazine. .

The term "carbonyl" as used herein refers to -C (O) -.

The term "carboxyl" as used herein refers to -COOH or its corresponding carboxylate salts, for example -COONa, etc. The term "carboxyl" also includes "carboxycarbonyl", for example a carboxyl group attached to a carbonyl group, for example, -C (O) -COOH or salts such as -C (O) -COONa, etc.

The term "cyano" as used herein refers to -CN.

The term "cycloalkoxy" as used herein refers to a cycloalkyl group attached to an oxygen.

The term "cycloalkyl" as used herein refers to a cyclic, bicyclic or bicyclic saturated or unsaturated hydrocarbon group with 3-12 carbon or 3-8 carbon bridge, referred to herein as "C3- cycloalkyl. C8) ”, derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes and cyclopentenes. The cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone , nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. The cycloalkyl groups may be condensed to other saturated or unsaturated cycloalkyl groups, aryl or heterocyclyl.

The term "dicarboxylic acid" as used herein refers to a group containing at least two carboxylic acid groups such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylic acids include alkyl dicarboxylic acids. The dicarboxylic acids may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl , ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include, but are not limited to succinic acid, glutaric acid, adipic acid, subic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+) / (-) - malic, (+) / (-) tartaric acid, isophthalic acid and terephthalic acid. The dicarboxylic acids further include carboxylic acid derivatives thereof, such as anhydrides, imides, hydrazides, etc., for example, succinic anhydride, succinimide, etc.

The term "ester" refers to the structure -C (O) O-, -C (O) O-Rj-, -RkC (O) O-Rj-, or -RkC (O) O-, in which Or it does not bind hydrogen and Rj and Rk can be independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, heterocyclyl. Rk can be a hydrogen, but Rj cannot be hydrogen. The ester can be cyclic, for example the carbon atom and Rj, the oxygen atom and Rk, or Rj and Rk can be joined to form a 3 to 12 member ring. Exemplary esters include, but are not limited to, alkyl esters in which at least one of Rj or Rk is alkyl, such as -OC (O) alkyl, -C (O) -O-alkyl-, - alkyl-C (O) -O-alkyl-, etc. Exemplary esters also include aryl or heteroaryl esters, for example in which at least one of Rj or Rk is a heteroaryl group such as pyridine, pyridazine, pyrimidine and pyrazine, such as a nicotinate ester. Exemplary esters also include inverse esters having the structure -RkC (O) O-, in which oxygen binds to the original molecule. Exemplary reverse esters include succinate, D-argininate, L-argininate, L-lysinate and D-lysinate. The esters also include carboxylic acid anhydrides and acid halides.

The term "ether refers to the structure -RlO-Rm-, in which Rl and Rm can independently be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl or ether. The ether can be attached to the original molecular group through Rl or Rm. Exemplary ethers include, but are not limited to, alkoxyalkyl and alkoxyaryl groups. The ethers also include polyethers, for example, in which one or both of R1 and Rm are ethers.

The terms "halo" or "halogen" or "Hal" as used herein refer to F, CI, Br or I.

The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more halogen atoms. "Haloalkyl groups" also encompass alkenyl or alkynyl groups substituted with one or more halogen atoms.

The term "heteroaryl" as used herein refers to a mono, bi or multicyclic aromatic ring system containing one or more heteroatoms, for example 1 to 3 heteroatoms, such as nitrogen, oxygen and sulfur. Heteroaryl groups may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryl groups may also be condensed to non-aromatic rings. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3) - and (1,2,4) -triazolyl, pyrazinyl , pyrimidyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl, phenyl, isoxazolyl and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, a monocyclic aromatic ring, in which the ring comprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to herein as "heteroaryl (C2- C5) ”

The terms "heterocycle", "heterocyclyl" or "heterocyclic" as used herein refer to a saturated, unsaturated, 3, 4, 5, 6 or 7-membered ring containing one, two or three independently selected heteroatoms of nitrogen, oxygen and sulfur. The heterocycles may be aromatic (heteroaryl groups) or non-aromatic. The heterocycles may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl , hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heterocycles also include bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is condensed to one or two rings independently selected from aryl, cycloalkyl and heterocycles groups. The heterocycles for example include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl , isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloílo , tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl and triazolyl.

The terms "hydroxy" and "hydroxyl" as used herein refer to -OH.

The term "hydroxyalkyl" as used herein refers to a hydroxyl attached to an alkyl group.

The term "hydroxyaryl" as used herein refers to a hydroxyl attached to an aryl group.

The term "ketone" as used herein refers to the structure -C (O) -Rn (such as acetyl, -C (O) CH3) or -Rn-C (O) -Ro-. The ketone can be linked to another group through Rn or Ro. Rn or Ro can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or Rn or Ro can be joined to form a 3 to 12 membered ring.

The term "monoester" as used herein refers to an analogue of a dicarboxylic acid in which one of the carboxylic acids is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or a salt of an acid. carboxylic. Examples of monoesters include, but are not limited to, monoesters of succinic acid, glutaric acid, adipic acid, subic acid, sebacic acid, azelaic acid, oxalic and maleic acids.

The term "nitro" as used herein refers to -NO2.

The term "perfluoroalkoxy" as used herein refers to an alkoxy group in which all of the hydrogen atoms have been replaced by fluorine atoms.

The term "perfluoroalkyl" as used herein refers to an alkyl group in which all hydrogen atoms have been replaced by fluorine atoms. Exemplary perfluoroalkyl groups include, but are not limited to, C1-5 perfluoroalkyl, such as trifluoromethyl, etc.

The term "perfluorocycloalkyl" as used herein refers to a cycloalkyl group in which all hydrogen atoms have been replaced by fluorine atoms.

The term "phenyl" as used herein refers to a 6-membered carbocyclic aromatic ring. The phenyl group may also be fused to a cyclohexane or cyclopentane ring. The phenyl group may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.

The term "phosphate" as used herein refers to the structure -OP (O) O2-, -RxP (O) O2-, -OP (O) O2Ry- or -RxOP (O) O2Ry-, in which Rx and Ry can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, hydrogen.

The term "sulfide" as used herein refers to the structure -RzS-, in which Rz can be alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl. The sulfide can be cyclic, forming a ring of 3 to 12 members. The term "alkyl sulfide" as used herein refers to an alkyl group attached to a sulfur atom.

The term "sulfinyl" as used herein refers to the structure -S (O) O-, -RpS (O) O-, -RpS (O) ORq- or -S (O) ORq-, wherein Rp and Rq can be alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxyl. Exemplary sulfinyl groups include, but are not limited to, alkylsulfinyl groups in which at least one of Rp or Rq is alkyl, alkenyl or alkynyl.

The term "sulfonamide" as used herein refers to the structure - (Rr) -NS (O) 2-Rs- or -Rt (Rr) -NS (O) 2-Rs, in which Rt , Rr and Rs can be, for example, hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl. Exemplary sulfonamides include alkylsulfonamides (for example, in which Rs is alkyl), arylsulfonamides (for example, in which Rs is aryl), cycloalkyl sulfonamides (for example, in which Rs is cycloalkyl) and heterocyclylsulfonamides (for example , in which Rs is heterocyclyl), etc.

The term "sulfonate" as used herein refers to -OSO3-. Sulfonate includes salts such as -OSO3Na, -OSO3K, etc. and the acid -OSO3H.

The term "sulfonic acid" refers to -SO3H- and its corresponding salts, for example -SO3K-, -SO3Na-.

The term "sulfonyl" as used herein refers to the structure RuSO2-, wherein Ru can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocyclyl, for example, alkylsulfonyl. The term "alkylsulfonyl" as used herein refers to an alkyl group attached to a sulfonyl group. The "alkylsulfonyl" groups may optionally contain alkenyl or alkynyl groups.

The term "thioketone" refers to the structure -Rv-C (S) -Rw-. The ketone can join another group through Rv or Rw. Rv or Rw can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl, or Rv or Rw can be joined to form a 3 to 12 membered ring.

The groups "alkyl", "alkenyl", "alkynyl", "alkoxy", "amino" and "amide" may be substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl , amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulphide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido and N. The substituents may be branched to form a substituted or unsubstituted heterocycle or cycloalkyl.

As used herein, a "suitable substituent" refers to a group that does not nullify the pharmaceutical utility or for synthesis of the compounds of the invention or intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: C1-22, C1-8 and C16 alkyl, alkenyl or alkynyl; C1-6 aryl, C2-5 heteroaryl; C3-7 cycloalkyl; C1-22, C1-8 and C1-6 alkoxy; C6 aryloxy; -CN; -OH; oxo; halo, carboxyl; amino, such as -NH (C1-22 alkyl, C1-8 or C1-6), -N (C1-22 alkyl, C1-8 and C1-6) 2, -NH (aryl (C6)) or -N (aryl (C6)) 2; formyl; ketones, such as -CO (C1-22 alkyl, C1-8 and C1-6), esters of -CO (aryl (C6)), such as -CO2 (C1-22 alkyl, C1-8 and C16) and - CO2 (C6 aryl). One skilled in the art can easily choose a suitable substituent based on the stability and the pharmacological and synthetic activity of the compound of the invention.

The term "pharmaceutically acceptable carrier" as used herein refers to each and every solvent, dispersion media, coatings, isotonic and absorption delay agents, and the like, which are compatible with administration. Pharmaceutical The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds that provide complementary, additional or enhanced therapeutic functions.

The term "pharmaceutically acceptable composition" as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

The term "pharmaceutically acceptable prodrugs" as used herein represents those prodrugs of the compounds of the present invention that are, within the scope of reasonable medical judgment, suitable for use in contact with the tissues of humans and animals. inferior without excessive toxicity, irritation, allergic response, in accordance with a reasonable risk / benefit ratio, and effective for its intended use, as well as the zwitterionic forms, when possible, of the compounds of the invention. An analysis is provided in Higuchi et al., "Pro-drugs as Novel Delivery systems", ACS Symposium Series, vol. 14, and in Roche, E.B., ed. Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

The term "pharmaceutically acceptable salt (s)" refers to salts of acidic or basic groups that may be present in the compounds used in the present compositions. The compounds included in the present compositions that are of a basic nature can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, that is, salts containing pharmacologically acceptable anions, which include but are not limited to sulfate salts. , citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tanate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, sucrate, format, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1'-methylene-bis- (2-hydroxy-3-naphthoate )). The compounds included in the present compositions that include an amino moiety can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. The compounds included in the present compositions, which are acidic in nature, can form base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium and iron salts.

The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term "stereoisomers" when used herein consists of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R" or "S", depending on the configuration of the substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. The stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated as "(±)" in the nomenclature, but one skilled in the art will recognize that a structure may implicitly indicate a chiral center.

The individual stereoisomers of the compounds of the present invention may be prepared by synthesis from commercially available starting materials containing asymmetric or stereogenic centers, or by the preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. . These resolution methods are shown by way of example by (1) binding a mixture of enantiomers to a chiral auxiliary agent, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary agent, (2) salt formation using an optically active resolution agent, or (3) direct separation of the mixture of optical enantiomers in chiral chromatographic columns. Stereoisomeric mixtures can also be resolved in their component stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high resolution liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent Stereoisomers can also be obtained from stereomerically pure intermediates, reagents and catalysts by well known methods of asymmetric synthesis.

There may also be geometric isomers in the compounds of the present invention. The present invention encompasses the various geometric isomers and mixtures thereof that result from the arrangement of the substituents around a carbon-carbon double bond or the arrangement of the substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures representing double bonds encompass both E and Z isomers.

Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," wherein "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond. The arrangements of the substituents around a carbocyclic ring are designated "cis" or "trans." The term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents on opposite sides of the plane of the ring. Mixtures of compounds in which the substituents are arranged both on the same side and on opposite sides of the plane of the ring are designated as "cis / trans".

Embodiments of the Invention

The following is a list of specific exemplary embodiments that are encompassed by the invention;

1. A compound of formula II for use to increase the expression of ApoA-I in a mammal:

Formula II

in which: X is N; R1 and R3 are each independently selected from alkoxy and hydrogen; R2 is selected from alkoxy, alkyl and hydrogen; R6 and R8 are each independently selected from alkyl, alkoxy, chloride and hydrogen; R4 and R5 are hydrogen; R7 is selected from amino, hydroxyl, alkoxy and alkyl substituted with a heterocyclyl, or two adjacent substituents selected from R6, R7 and R8 are connected to form a heterocyclyl; each W is independently selected from C and N; p is 1, with the exception that when W is N, then p is 0; wherein the groups "alkyl", "alkenyl", "alkynyl", "alkoxy", "amino" and "amide" may be substituted with or

interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl , hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido and N;

with the proviso that if R2 is selected from alkoxy or hydrogen, then at least one of R1 and R3 is alkoxy;

with the proviso that if R7 is selected from hydroxyl or alkoxy, then at least one of R6 and R8 is selected independently of alkyl, alkoxy and chloride; with the proviso that if for W- (R7) p, W is N and p is 0, then at least one of R6 and R8 is chloride; and pharmaceutically acceptable salts and hydrates thereof.

2.

 The compound for use according to embodiment 1, wherein at least one of R6 and R8 is selected from alkyl, alkoxy and chloride.

3.

The compound for use according to embodiment 1, wherein R6 and R8 are each hydrogen and W- (R7) p is C- (R7) 1.

Four.

 The compound for use according to embodiment 1 or embodiment 2, wherein neither R6 nor R8 is hydrogen.

5.

The compound for use according to any one of embodiments 1, 2 and 4, wherein R1 and R3 are alkoxy; R6 and R8 are alkyl; and R7 is alkoxy substituted with a hydroxyl.

6.

 The compound for use according to embodiment 1, wherein R7 is selected from hydroxyl and alkoxy.

7.

 The compound for use according to embodiment 1, wherein the compound of formula II is 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 7 );

2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 4); 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 7); 3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one (example 8); 2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 9);

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 10); 2- (4-bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one (example 11); 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one (example 12); 2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 13); 2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrid [2,3-d] pyrimidin-4 (3H) -one (example 14);

2- (2-Chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 15); 5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one (example 16); 2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 17); N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (example 18); 2- (4- (2-Aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 18); Y

4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (example 20).

8. The compound for use according to embodiment 1, wherein R7 is an amino or alkoxy group selected from the group represented by formula III:

Formula III

20 in which; A is selected from O and N; n is selected from 0, 1, 2, 3, 4 and 5; B is selected from -C (O) N (Rh) 2-, -S (O) 2N (Rh) 2-, -C (O) -, -S (O) 2 -, - C (O) O- , in which each Rh is selected

alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl e

Hydrogen; and R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen.

In another embodiment, if A is O and B is -C (O) NH-, then R20 is not an unsaturated cycloalkyl group.

9. The compound for use according to embodiment 8, wherein the compound of formula II is selected from:

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (example 19); N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (example 21); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide

(example 22); 4-Chloro-N- (2- (4-5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (example 23);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide (example 24); 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl propylcarbamate (example 25); 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl methylcarbamate (example 26);

5 N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide (example 27); 2- (4- (5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate (example 28);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (example 29);

10 N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide

(example 30); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzamide (example 31);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) acetamide (example 32);

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide (example 33); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) isobutyramide (example 34); 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-methylurea (example 35); 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea (example

36);

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea (example 37); and 3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethylurea (example 38).

10. The compound for use according to embodiment 1, wherein the therapeutically effective amount of the compound of formula II is to be administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

The compound for use according to embodiment 1, further comprising treating or preventing a cardiovascular disorder, related to cholesterol or lipids.

12. A compound of formula II:

Formula II

30 in which: X is N; R1 and R3 are each independently selected from alkoxy and hydrogen; R2 is selected from alkoxy, alkyl and hydrogen; R6 and R8 are each independently selected from alkyl, alkoxy, chloride and hydrogen;

R4 and R5 are hydrogen; R7 is selected from amino, hydroxyl, alkoxy and alkyl substituted with a heterocyclyl; or two adjacent substituents selected from R6, R7 and R8 are connected to form a heterocyclyl; each W is independently selected from C and N; p is 1, with the exception that when W is N, then p is 0; with the proviso that if R2 is selected from alkoxy or hydrogen, then at least one of R1 and R3 is alkoxy; with the proviso that if R7 is selected from hydroxyl or alkoxy, then at least one of R6 and R8 is selected

independently of alkyl, alkoxy and chloride; with the proviso that if for W- (R7) p, W is N and p is 0, then at least one of R6 and R8 is chloride; and pharmaceutically acceptable salts and hydrates thereof.

13.

The compound according to embodiment 12, wherein the compound is 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 7).

14.

The compound according to embodiment 12, wherein the compound of formula II is selected from: 2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 4); 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 7); 2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 9); 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 10); 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one (example 11); 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one (example 12); 2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 13); 2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrid [2,3-d] pyrimidin-4 (3H) -one (example 14); 2- (2-Chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 15); 5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one (example 16); 2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 17); N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (example 18); 2- (4- (2-Aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (example 18); and 4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (example 20).

fifteen.

The compound according to embodiment 12, wherein R7 is an amino or alkoxy group selected from the group represented by formula III:

Formula III

in which:

A is selected from O and N;

n is selected from 0, 1, 2, 3, 4 and 5;

14

B is selected from -C (O) N (Rh) 2-, -S (O) 2N (Rh) 2-, -C (O) -, -S (O) 2-, -C (O) O- , wherein each Rh is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen; Y

R20 is selected from (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen.

In another embodiment, if A is O and B is -C (O) NH-, then R20 is not an unsaturated cycloalkyl group.

16. The compound according to embodiment 15, wherein the compound of formula II is selected from N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) - 2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (example 19); N1- (2- (4- (5,7-dimethoxy4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (example 21); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide (example 22); 4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (example 23); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dlhydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide (example 24); 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl propylcarbamate (example 25); 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl methylcarbamate (example 26); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide (example 27); 2- (4- (5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate (example 28); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide (example 29); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide (example 30); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) 4-methoxybenzamide (example 31); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) acetamide (example 32); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide (example 33); N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) isobutyramide (example 34); 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-methylurea (example 35); 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea (example 36 ); 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea (example 37); and 3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethylurea (example 38).

17. A pharmaceutical composition comprising a compound according to embodiment 12 and a pharmaceutically acceptable carrier.

18. A compound according to embodiment 12 for use in the treatment of cardiovascular disorders, related to cholesterol or lipids.

19. A compound according to embodiment 12 for use in increasing the expression of ApoA-I in a mammal.

Pharmaceutical formulations and use in treatment

The present disclosure also discloses pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those that are suitable for oral, rectal, topical, buccal and parenteral administration (for example subcutaneous, intramuscular, intradermal or intravenous), although the most appropriate form of administration in a given case will depend on the degree and severity of the state being treated and the nature of the particular compound being used.

Formulations suitable for oral administration may be presented in differentiated units, such as capsules, seals, lozenges or tablets, each containing a predetermined amount of the compound as powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil in water or water in oil emulsion. As indicated, such formulations can be prepared by any suitable pharmacy method that includes the step of associating the active compound and the carrier or excipient (which may constitute one or more auxiliary components). The carrier must be acceptable in the sense of being compatible with the other components of the formulation and must not be harmful to the recipient. The carrier may be a solid or a liquid, or both, and may be formulated with the compound as a unit dose formulation, for example, a tablet, which may contain from about 0.05% to about 95% by weight of the active compound Other pharmacologically active substances may also be present including other compounds. The formulations of the invention can be prepared by any of the well known pharmacy techniques that essentially consist of mixing the components.

For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid compositions can be prepared which can be administered pharmacologically, for example, by dissolving, dispersing, etc., of an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, solution. saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension. In general, suitable formulations can be prepared by uniformly and intimately mixing the active compound with a finely divided solid liquid or carrier, or both, and then, if necessary, forming the product. For example, a tablet can be prepared by compressing or molding a powder or granules of the compound, optionally with one or more auxiliary components. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a fluid form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent and / or surfactant agent (s). / dispersant (s). Molded tablets can be prepared by molding, in a suitable machine, the powdered compound moistened with an inert liquid diluent.

Formulations suitable for oral (sublingual) administration include lozenges comprising a compound in a flavored base, usually sucrose and gum arabic or gum tragacanth, and tablets comprising the compound in an inert base such as gelatin and glycerin or sucrose and gum arabic

The formulations of the present invention suitable for parenteral administration comprise sterile aqueous preparations of the compounds, which are approximately isotonic with respect to the blood of the intended recipient. These preparations are administered intravenously, although administration can also be performed by subcutaneous, intramuscular or intradermal injection. Such preparations can be conveniently prepared by mixing the compound with water and making the resulting solution sterile and isotonic with respect to blood. Injectable compositions according to the invention may contain from about 0.1 to about 5% w / w of the active compound.

Formulations suitable for rectal administration are presented as unit dose suppositories. These can be prepared by mixing the compound with one or more conventional solid carriers, for example, cocoa butter, and then forming the resulting mixture.

Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, spray or oil. Carriers and excipients that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present at a concentration of from about 0.1% to about 15% w / w of the composition, for example, from about 0.5 to about 2%.

The amount of active compound administered may depend on the subject being treated, the weight of the subject, the manner of administration and the judgment of the prescribing physician. For example, a dosing schedule may involve daily or semi-daily administration of the encapsulated compound at a perceived dosage of about 1 µg to about 1000 mg. In another embodiment, intermittent administration, such as monthly or annually, of a dose of the encapsulated compound may be employed. The encapsulation facilitates access to the site of action and allows the administration of the active ingredients simultaneously, theoretically producing a synergistic effect. According to the usual dosage regimens, doctors will easily determine the optimal dosages and will be able to easily modify the administration to achieve such dosages.

A therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic efficacy of the compound. The dosages, however, can be varied depending on the requirements of the patient, the severity of the condition being treated, and the compound being used. In one embodiment, the therapeutically effective amount of a compound disclosed is sufficient to establish a maximum plasma concentration. Preliminary doses as determined, for example, according to animal tests, and the increase in dosage scale for human administration are performed according to practices accepted in the art.

Toxicity and therapeutic efficacy can be determined by usual pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD50 (the lethal dose for 50% of

the population) and the ED50 (the therapeutically effective dose in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / DE50. Compositions with large therapeutic indices are preferred.

Data obtained from cell culture assays or animal studies can be used in the formulation of a range of dosages for use in humans. Therapeutically effective dosages achieved in an animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, for example, Freireich et al., Cancer Chemother. Reports 50 (4): 219-244 (1966) and table 1 for equivalent surface area dosage factors).

Table 1

A: From:

Mouse (20 g) Rat (150 g) Monkey (3.5 kg) Dog (8 kg) Human being (60 kg)

Mouse

one 1/2 1/4 1/6 1/12

Rat

2 one 1/2 1/4 1/7

Monkey

4 2 one 3/5 1/3

Dog

6 4 3/5 one 1/2

Human being

12 7 3 2 one

The dosage of such compounds is preferably within a range of circulating concentrations that includes the ED50 with little or no toxicity. The dosage may vary within this range depending on the pharmaceutical form used and the route of administration used. Generally, a therapeutically effective amount may vary with the age, condition and sex of the subject, as well as the severity of the medical condition in the subject. The dosage can be determined by a doctor and adjusted, if necessary, to suit the observed effects of the treatment.

In one embodiment, a compound as disclosed herein, or a pharmaceutically acceptable salt or hydrate thereof, is to be administered in combination with another therapeutic agent. The other therapeutic agent may provide additive or synergistic value in relation to the administration of a compound of the present invention alone. The therapeutic agent can be, for example, a statin; a PPAR agonist, for example, a thiazolidinedione or fibrate; a niacin, an agonist of RVK, FXR or LXR; a bile acid reuptake inhibitor, a cholesterol absorption inhibitor; an inhibitor of cholesterol synthesis; an ion exchange resin; an antioxidant; an acylCoA-cholesterol acyltransferase inhibitor (ACAT inhibitor); a thyrophostin; a sulfonylurea based drug; a biguanide; an alpha-glucosidase inhibitor; an apolipoprotein E regulator; an HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein; an LDL decrease drug; an HDL lifting drug; an HDL enhancer; a regulator of the apolipoprotein and / or apolipoprotein A-IV genes; or any cardiovascular drug.

In one embodiment, a therapeutically effective amount of a disclosed compound is used to treat or prevent cardiovascular disease, cholesterol or lipid-related disorders in a mammal (eg, a human being). The compound disclosed can be administered as a pharmaceutically acceptable composition, which comprises a compound disclosed and a pharmaceutically acceptable carrier.

As used herein, the term "cardiovascular disease" refers to diseases and disorders of the heart and circulatory system. Exemplary cardiovascular diseases, including cholesterol or lipid-related disorders, include, but are not limited to acute coronary syndrome, angina, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, stabilization of the coronary plaque, dyslipidemias, dyslipoproteinemias, endothelial dysfunctions, familial hypercholesterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, ischemia, heart disease , cardiac ischemia, metabolic syndrome, multiple infarction dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, atherosclerosis of the artery Renal ia, rheumatic heart disease, stroke, thrombotic disorder, transient ischemic attacks and lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes mellitus, syndrome X, impotence, multiple sclerosis, Parkinson's diseases and inflammatory diseases.

One embodiment provides compounds for use in altering lipid metabolism in a patient, for example, increasing the ratio of HDL with respect to LDL or ApoA-I with respect to ApoB in the blood of a patient, in which it is to be administered a composition of the invention in an amount effective to alter lipid metabolism.

One embodiment provides compositions for use in raising the levels of ApoA-I associated molecules, such as HDL, in the blood of a mammal, in which a composition comprising a compound or composition disclosed is to be administered. in an amount effective to raise the levels of proteins associated with ApoA-I and HDL in the mammal.

In one embodiment, "treatment" or "treating" refers to an improvement of a disease or disorder, or at least an appreciable symptom thereof. In another embodiment, "treatment" or "treating" refers to an improvement of at least one measurable physical parameter, not necessarily appreciable by the patient. In yet another embodiment, "treatment" or

"Treat" refers to inhibiting the progression of a disease or disorder, either physically, for example, the stabilization of an appreciable symptom, or physiologically, for example, the stabilization of a physical parameter, or both. In yet another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or disorder. For example, treating a cholesterol disorder may include lowering blood cholesterol levels.

An embodiment provides a compound for administration to a patient, such as a human being, as a preventive measure against cardiovascular diseases, including disorders related to cholesterol or lipids. As used herein, "prevention" or "prevent" refers to a reduction in the risk of acquiring a given disease or disorder. An additional aspect provides a composition / compound for use in preventing the development of arteriosclerotic lesion in a mammal, including the development of

15 new arteriosclerotic lesions. In another aspect, the present invention provides a composition / compound for use in the regression of arteriosclerotic lesions.

In another embodiment, the present compositions are to be administered as a preventive measure to a patient, such as a human being who has a genetic predisposition for cardiovascular disease, including disorders related to cholesterol or lipids, for example familial hypercholesterolemia, hyperlipidemia

20 combined family, atherosclerosis, dyslipidemia, dyslipoproteinemia or Alzheimer's disease.

In another embodiment, the compositions of the invention will be administered as a preventive measure to a patient who has a non-genetic predisposition for cardiovascular disease, including cholesterol or lipid-related disorders. Examples of such non-genetic predispositions include, but are not limited to, cardiac bypass surgery and percutaneous transluminal coronary angioplasty, which often lead to

25 restenosis, an accelerated form of atherosclerosis; diabetes in women, which often leads to polycystic ovarian disease; and cardiovascular disease, which often leads to impotence.

Angioplasty and open heart surgery, such as coronary bypass surgery, may be required to treat cardiovascular diseases, such as atherosclerosis. These surgical interventions involve using implants and / or invasive surgical devices, and are associated with a high risk of restenosis and thrombosis. By

Accordingly, the compounds of the invention can be used as coatings in surgical devices (for example, catheters) and implants (for example, stents) to reduce the risk of restenosis and thrombosis associated with invasive procedures used in the treatment of cardiovascular diseases.

In another embodiment, the present compositions can be used for the prevention of a disease or disorder and to simultaneously treat another (e.g., prevention of polycystic ovarian disease while

35 diabetes is treated; impotence prevention while treating cardiovascular disease).

The diseases and conditions associated with "diabetes mellitus" as defined herein refer to chronic metabolic disorder (s) caused by an absolute or relative insulin deficiency including, but not limited to hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, macular degeneration, cataracts, nephropathy

40 diabetic, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, ulcerative colitis, skin and connective tissue disorders, foot ulcers, metabolic acidosis, arthritis, osteoporosis and impaired glucose tolerance.

COMPOUND PREPARATION

The compounds of the invention by way of example represented by the general formula A:

in which:

Ra may be selected from groups that include, but are not limited to, alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ether, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen and hydroxyl; Rb can be selected from groups that include, but are not limited to, alkyl and hydrogen; X may be selected from, for example, CRc, N and NRc, in which Rc represents substituents such as alkyl, alkenyl, alkynyl and hydrogen; And it can be selected from, for example, CO, CS and SO2-; and Z3 can be a single or double bond; they can be synthesized from readily available starting materials as explained briefly in the diagrams by way of example below. It should be noted that these designations are non-limiting examples.

Scheme 1

Scheme 1 illustrates that condensation followed by oxidation of amide 1 and aldehyde 2 can provide quinazolinone 3. Condensation can occur under a variety of conditions, such as NaHSO3 and p-TsOH 10 in dimethylacetamide, I2 in the presence of K2CO3 , and treatment with catalytic trifluoroacetic acid followed by oxidation with DDQ.

Scheme 2

Condensation of the amide 4 with nitrile 5 in the presence of n-BuLi can provide isoquinolinone 6, such as shown in scheme 2.

Scheme 3

Scheme 3 provides a method for synthesizing benzothiazine 1,1-dioxide 9. The amide coupling of sulfonamide 7 with carboxylic acid 8 may be followed by treatment with n-BuLi to provide 9.

20 Examples

Abbreviations used herein indicate the following compounds, reagents and substituents: acetic acid (AcOH); 2,2’-azobisisobutyronitrile (AIBN); N-bromosuccinimide (NBS); N-tert-butoxycarbonyl (Boc); tbutyldimethylsilyl (TBDMS); m-chloroperoxybenzoic acid (mCPBA); dimethylaminopyridine (DMAP); dichloromethane (DCM); dimethylformamide (DMF); dimethylsulfoxide (DMSO); ethanol (EtOH); ethyl acetate (EtOAc); 1-ethyl-3- (3

Dimethylaminopropyl) carbodiimide (EDCI); 1-hydroxybenzotriazole (HOBt); iodomethane (MeI); lithium hexamethyldisilazide (LHMDS); methanol (MeOH); methoxymethyl (MOM); tetrahydrofuran (THF); triethylamine (Et3N); lithium aluminum hydride (LAH); p-toluenesulfonic acid (p-TSA); tetrabutylammonium fluoride (TBAF); N-methyl morpholine (NMM); N, N-dimethylacetamide (DMA); twice a day (b.i.d.), once a day (q.d.).

Example 1 (reference example)

3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one

To a suspension of 2-methyl-4,6-dimethoxybenzoic acid (2.61 g, 13.1 mmol) in CH2Cl2 (50 ml), oxalyl chloride (3.38 g, 26.6 mmol) was added and The mixture was stirred at room temperature for 16 h. The solvent and excess oxalyl chloride were removed under reduced pressure. The solid was dissolved in CH2Cl2 (10 ml) and methylamine (1.24 g, 39.9 mmol) with cooling and stirred at room temperature for 4 h. The solvent was removed and the crude product was purified by chromatography using 5% methanol in CH2Cl2 to give the amide (2.27 g, 82%). To a solution of the above amide (2.27 g, 10.9 mmol) in THF (50 ml), n-butyllithium (9.98 ml, 25.0 mmol, 2.5 M solution was added slowly in hexane) under nitrogen with cooling, keeping the temperature below 20ºC. The mixture was stirred for 1 h at 0 ° C, then cooled to -50 ° C, and a solution of 4-O-TBDMS-3,5-dimethylbenzonitrile (2.97 g, 11.39 mmol) in THF (10 mL) was quickly added ), the cooling bath was removed and the mixture was stirred for 16 h at room temperature. A saturated aqueous NH4Cl solution was added with cooling and the phases were separated. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated to give 3.9 g of the crude product mixture. A suspension of the crude product mixture (3.9 g) in ethanol (20 ml) was heated with conc. HCl. (2 ml) at 80 ° C for 2 h. The reaction mixture was cooled to room temperature and the solvent was removed. The solid was dissolved in water and neutralized by NaHCO3, followed by extraction with CH2Cl2. The product was purified by chromatography to give two products: 3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxy-2-methylisoquinolin-1 (2H) -one (128 mg, 5%) and 3- ( 4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one (340 mg, 9%). Data selected for 3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one: MS (ES) m / z: 326.00; m.p. 226-227 ° C.

Example 2 (reference example)

3- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one

To a solution of 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in DMF (100 ml), NaH (1.065 g, 26.63 mmol) and (2-bromoethoxy) were added -terc-butyldimethylsilane (1.85 g, 8.15 mmol). The reaction mixture was stirred for 10 d at room temperature under nitrogen. The reaction mixture was poured into ice water and the products were extracted with ethyl acetate. The organic phase was separated, washed with water, dried and concentrated to give the crude product, which was purified by column chromatography to give 1.9 g of the structural element of ring B with a yield of 92%.

N-Butyllithium (2.84 ml, 7.1 mmol, 2.5 M solution in hexane) was slowly added to a solution of 2,4-dimethoxy6-methylbenzamide (650 mg, 3.1 mmol) in THF ( 30 ml), under nitrogen with cooling (ice-salt bath), keeping the temperature below 20ºC. After completion of the addition, the mixture was stirred for 1 h at 0 ° C, and then cooled to -50 ° C and a solution of 4- (2-tert-butyldimethylsilyloxy) ethoxy) -3,5-dimethylbenzonitrile (the structural element of ring B) was quickly added , above) (996 mg, 3.26 mmol) in THF (10 ml). The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred for 16 h at room temperature. A saturated NH4Cl solution was added with cooling, and the phases were separated. The organic phase was washed with water, brine, dried over Na2SO4 and concentrated to give 1.2 g of crude product.

The above crude product (1.2 g) was treated with ethanol (10 ml) and conc. HCl. (2 ml) at 80 ° C for 1 h. The solvent was removed and the residue was dissolved in methanol and neutralized by NaHCO3. The solvent was evaporated and the crude product was purified by column chromatography to give 3- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,8-dimethoxylsoquinolin-1 (2H) -one (100 mg, 11% ). Selected data: m.p. 193-195 ° C.

Example 3 (reference example)

3- (4-Hydroxy-3,5-dimethylphenyl) -7- (morpholinomethyl) isoquinolin-1 (2H) -one Hydrogen bromide in acetic acid (13 ml, 33% by weight) was added to an acid mixture 2-methylbenzoic

(4.08 g, 30 mmol), paraformaldehyde (2.50 g, 83.0 mmol) and o-phosphoric acid (7 ml, 85%). The reaction mixture was stirred at 115 ° C for 15 h. It was cooled to room temperature and poured into ice water. A white precipitate formed. The mixture was extracted with ethyl acetate (300 ml). The organic phase was washed with water (100 ml), brine (100 ml) and dried over anhydrous Na2SO4. Solvent removal gave 6.84 g of a white solid, which was used in the next step without further purification. The above compound (6.8 g) was dissolved in anhydrous dichloromethane (150 ml). Oxalyl chloride (7.8 ml) was added dropwise. After the addition was complete, 3 drops of anhydrous DMF were added. A vigorous reaction occurred and stirring was continued overnight. The solvent and excess oxalyl chloride were removed under reduced pressure and the residue was dried in vacuo to give 7.02 g of a brown liquid, which was used in the next step without further purification. The above compound (7.02 g, 28.36 mmol) was dissolved in anhydrous THF (60 ml) and cooled to 0 ° C. A solution of N-methylamine (2.0 M in THF, 19 ml, 38.03 mmol) was added dropwise under nitrogen. Stirring was continued for 15 min. at 0 ° C. The ice bath was removed, and stirring was continued at room temperature for 3 h. A white precipitate formed. Water (100 ml) was added and the mixture was extracted with ethyl acetate (150 ml). The organic phase was separated, washed with water (50 ml), saturated NaHCO3 solution (2x50 ml), water (50 ml) and brine (50 ml), and dried over anhydrous Na2SO4. Solvent removal gave 5.64 g of 5-bromomethyl-2, N-dimethylbenzamide as a white solid that was used in the next step without further purification. To a solution of the above compound (2.42 g, 10 mmol) in anhydrous THF was added morpholine (1.92 g, 22 mmol) at room temperature under nitrogen. A white precipitate formed. Stirring was continued overnight. Water (100 ml) was added and the mixture was extracted with ethyl acetate (150 ml). The organic phase was separated, washed with water (50 ml) and brine (50 ml) and dried (Na2SO4). Solvent removal gave a colorless oil, which was purified by column chromatography (230-400 mesh silica gel; 0-5% methanol in CH2Cl2 as eluent) to give the desired benzamide intermediate (0.50 g yield, 20%). N-Butyllithium (1.6 M solution in hexanes, 4.1 ml, 6.6 mmol) was added dropwise to a solution of benzamide (0.5 g, 2.0 mmol) in anhydrous THF ( 4 ml) at -10 ° C over a period of 10 min. low nitrogen Stirring was continued at 0 ° C for 1 h. The reaction mixture was cooled to -50 ° C. A solution of 4- (tert-butyldimethylsilyloxy) -3,5-dimethylbenzonitrile (0.653 g, 2.5 mmol in anhydrous THF (3 mL) was added quickly. The cooling bath was removed and the mixture was allowed to warm reaction at room temperature Stirring was continued at room temperature for 1 h An aqueous solution of ammonium chloride (5 ml) was added followed by ethyl acetate (50 ml) The organic phase was separated, washed with water (5 ml) and dried (Na2SO4) Solvent removal gave 1.23 g of a pale yellow gummy material, which was used in the next step without further purification.The above compound was dissolved (1.2 g ) in 10 ml of anhydrous ethanol Conc. HCl (1 ml) was added and the mixture was refluxed for 15 min, then cooled to room temperature The solvent was removed under reduced pressure The crude compound was basified with methanolic ammonia and purified by chromatography in column (silica gel 230-400 mesh; 0-5% methanol in CH2Cl2 as eluent) to give 3 (4-hydroxy-3,5-dimethylphenyl) -7-morpholin-4-ylmethyl-2H-isoquinolin-1-one (35 mg) as a colored solid white (free base). To a solution of the above compound (35 mg) in CH2Cl2 (5 ml) and MeOH (1 ml) was added dropwise hydrogen chloride in ether (0.5 ml, 1.0 M) under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under vacuum to give 3- (4-hydroxy-3,5-dimethylphenyl) -7- (morpholinomethyl) isoquinolin-1 (2H) -one (36 mg, 93%) hydrochloride as a yellow solid. Selected data: m.p. 281-283 ° C (hydrochloride).

Example 4

2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

A solution of 3,5-dimethoxyaniline (199 g, 1.30 mol) in ether (5.0 L) was cooled to 0 ° C in a 3-mouth flask of 5 l. HCl gas (227 g) was bubbled through the solution over 45 min. After 45 min. at 10 ° C, the mixture was filtered, washed with isopropyl acetate (4 L), and dried overnight under high vacuum at 45 ° C to give the hydrochloride (242.3 g, 98%), as a white solid . A mixture of the above hydrochloride (20 g, 0.105 mol) and oxalyl chloride (33 ml) was heated in a 3-mouth flask equipped with a reflux condenser for 2 h with stirring (external temperature of 170 ° C), and the mixture was distilled off. oxalyl chloride of the reaction mixture. The flask was cooled to 0 ° C and methanol (40 ml) was added. The reaction mixture was heated to reflux for 45 min., Filtered while hot, and washed with methanol (80 ml) to give 4,6-dimethoxyisatin (17.2 g, 79%) as a colored solid. yellowish green. To a heated solution (external temperature of 70 ° C) of the isatin (182 g, 0.78 mol) in aqueous NaOH (40%, 1.5 L) was added H2O2 (35%, 405 ml) slowly at 2 h long After the addition of each portion of H2O2, the internal reaction temperature (initially 64 ° C) increased (to a maximum temperature of 80 ° C). After completion of the addition, the foaming reaction mixture was then stirred for an additional 2 h at 70 ° C, and the mixture was allowed to stir overnight while cooling to RT. Be

heated the mixture to 70 ° C. Additional H2O2 (75 ml) was added, and the mixture was stirred at 70 ° C for an additional 2 h until the reaction was complete. After cooling to 10 ° C (bath temperature), aqueous Na2S2O3 (150 ml, saturated) was added. The mixture was brought to pH 8 with HCl (37%, 1.6 L) and pH 6 with acetic acid (glacial, 75 ml), without allowing the reaction mixture to warm to more than 40 ° C. Filtration of the reaction mixture and washing with water (4 L) gave the expected amino acid as a tan solid (83.7 g, 55%). To a solution of the amino acid (82.7 g, 0.42 mol) in anhydrous THF (4.2 l) was added EDCl (89.2 g, 0.48 mol), HOBT (65 g, 0.48 mol ) and NMM (51.3 ml), and the mixture was allowed to stir at RT for 3 h. Aqueous NH3 (83 ml, 50%) was added, and the mixture was stirred at RT for 16 h. Water (1.25 L) was added, and the mixture was extracted with DCM (2 x 250 ml). The combined extracts were then washed with water (2x500 ml). Concentration, formation of a thick suspension with ether (550 ml), filtration and drying under high vacuum gave 2-amino-4,6-dimethoxybenzamide (46.7 g, 57%) as a brown solid.

2-Amino-4,6-dimethoxy-benzamide (1.06 g, 5.4 mmol), 3,5-dimethyl-4-hydroxybenzaldehyde (0.810 g, 5.4 mmol), K2CO3 (0.747 g, 5) were mixed , 4 mmol) and l2 (1,645 g, 6.5 mmol) in DMF (20 ml) and the reaction mixture was heated at 80 ° C for 12 h. It was cooled to RT and poured into crushed ice. The solid was collected and purified by column chromatography to give 2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.9 g, 51%) as a solid white. Selected data: m.p. 291-293 ° C.

Example 5 (reference example)

3- (4- (2-Hydroxy-2-methylpropoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one

To a solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.5 mmol) and 1-chloro-2-methylpropan-2-ol (8.85 g, 81.5 mmol) in ethanol ( 50 ml) was added potassium carbonate (7.5 g, 54 mmol) and water (5 ml). The reaction mixture was stirred at reflux for 24 h and cooled to RT. The precipitated solid was filtered off and washed with water. The solid was dissolved in ethyl acetate (100 ml), washed with water (50 ml), brine (50 ml), and dried over anhydrous Na2SO4. Solvent removal gave 4- (2-hydroxy-2-methylpropoxy) -3,5-dimethylbenzonitrile (2.9 g, 97%) as a white solid.

To a solution of 4- (2-hydroxy-2-methylpropoxy) -3,5-dimethylbenzonitrile (2.90 g, 13.2 mmol) in anhydrous DMF (20 ml) was added imidazole (2.7 g, 40 mmol) and tert-butyldimethylsilyl chloride (2.19 g, 14.6 mmol). The reaction mixture was stirred at RT under nitrogen for 3 d. Water (200 ml) was added and the mixture was extracted with ethyl acetate (200 ml). The organic phase was washed with water (2x100 ml) and brine (100 ml), and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude compound was purified by column chromatography to give 4- [2- (tert-butyldimethylsilyloxy) -2-methylpropoxy] -3,5-dimethylbenzonitrile (2.24 g, 54%). N-Butyllithium (6.2 ml, 6.6 mmol, 1.6 M solution in hexanes) was added to a solution of 2,4-dimethoxy-6-N-dimethylbenzamide (0.9 g, 4.3 mmol) in anhydrous THF (10 ml) dropwise at -10 ° C over a period of 10 min. low nitrogen Stirring was continued at 0 ° C for 1 h. The reaction mixture was cooled to -50 ° C. A solution of 4- [2- (tert-butyldimethylsilyloxy) -2-methylpropoxy] -3,5-dimethylbenzonitrile (1.68 g, 4.73 mmol) in anhydrous THF (5 ml) was quickly added. The cooling bath was removed and the reaction mixture was allowed to warm to RT. Stirring was continued at RT for 1 h. An aqueous solution of ammonium chloride (10 ml) was added followed by ethyl acetate (100 ml). The organic phase was separated, washed with water (10 ml) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude compound was purified by column chromatography (230-400 mesh silica gel; 0-5% methanol in CH2Cl2 as eluent) to give 3- {4- [2- ( tert-butyldimethylsilyloxy) -2-methylpropoxy] -3,5-dimethylphenyl} -6,8-dimethoxy-2H-isoquinolin-1-one (0.82 g, 37%), as a white solid.

The above compound (0.42 g, 0.82 mmol) was dissolved in anhydrous THF (20 ml). Tetrabutylammonium fluoride (4.1 ml, 1.0 M solution in THF) was added at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 min., Then at RT for 2 h and then stirred at 70 ° C for 24 h. The mixture was cooled to RT. Saturated aqueous ammonium chloride (30 ml) was added. The organic phase was separated, washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (230-400 mesh silica gel; 0-4% methanol in CH2Cl2 as eluent) to give 3- (4- (2-hydroxy-2-methylpropoxy) -3, 5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one (0.15-g, 46%), as a white solid. Selected data: MS (ES) m / z: 397.98; m.p. 252-254 ° C in decomposition.

Example 6 (reference example)

7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-1,6-naphthyridin-5 (6H) -one

A mixture of malonic acid (20 g, 192 mmol), 2,4,6-trichlorophenol (72 g, 365 mmol) and phosphorus oxychloride (38 ml, 403.2 mmol) was stirred for 12 h. The reaction mixture was cooled to 70 ° C and poured into ice water. The solid was collected by filtration, washed with water and dried to give bis- (2,4,6-trichloro-phenyl) ester of malonic acid (85 g, 95%). A solution of bis- (2,4,6-trichloro-phenyl) ester of malonic acid (85 g, 184 mmol) and ethyl 3-aminocrotonate (26.08 g, 201.9 mmol) in bromobenzene was stirred under reflux (100 ml) for 50 min. The reaction mixture was cooled to 50 ° C and diluted with EtOAc (260 ml). The solid was collected by filtration, washed with water, and dried to give 4,6-dihydroxy-2-methylnicotinic acid ethyl ester (31 g, 86%). A solution of 4,6-dihydroxy-2-methylnicotinic acid ethyl ester (31 g, 157 mmol) in phosphorus oxychloride (80 ml, 629 mmol) was stirred under reflux for 1.5 h. The extra phosphorus oxychloride was removed and the reaction mixture was poured into ice water. The solid was removed by filtration. The filtrate was extracted with dichloromethane (3x100 ml) and concentrated. The residue was further purified by column chromatography, to provide 4,6-dichloro-2-methylnicotinic acid ethyl ester (16.9 g, 46%). A solution of 4,6-dichloro-2-methylnicotinic acid ethyl ester (16.9 g, 71.3 mmol) in MeOH (60 ml) was mixed with sodium methoxide (58 ml, 258.68 mmol) and stirred at reflux for 12 h. The reaction was quenched by adding HOAc (50 ml). The mixture was diluted with water (200 ml), extracted with dichloromethane (3x100 ml) and concentrated. The residue was purified by column chromatography (SiO2, hexanes / EtOAc = 6: 1), to provide 4,6-dimethoxy-2-methylnicotinic acid methyl ester (10 g, 67%). A solution of 4,6-dimethoxy-2-methylnicotinic acid methyl ester (2.6 g, 12.3 mmol), lithium hydroxide (1.06 g, 44.08 mmol) in water (40) was stirred at reflux ml), MeOH (30 ml) and THF (20 ml) for 4 h. The reaction mixture was concentrated to dryness. The residue was mixed with HCl (conc., 20 ml) and concentrated again under high vacuum to dryness to provide crude 4,6-dimethoxy-2-methylnicotinic acid (quantitative yield). To a solution of 4,6-dimethoxy-2-methylnicotinic acid (2.5 g, 12.0 mmol) in dichloromethane (50 ml) and THF (50 ml) at room temperature was added oxalyl chloride (2.57 ml, 29.4 mmol) and DMF (3 drops). The reaction mixture was stirred at room temperature for 0.5 h, concentrated to dryness using a rotary evaporator to provide HCl salt of crude 4,6-dimethoxy-2-methylnicotinic acid chloride (2.8 g, quantitative) . A solution of 4,6-dimethoxy-2-methylnicotinic acid chloride chloride (4.8 g, 23.5 mmol) in dichloromethane (100 ml) was poured at room temperature into a beaker of ammonium hydroxide precipitates (200 ml). The reaction mixture was stirred at room temperature for 1 h, extracted with dichloromethane (3x100 ml), and concentrated using a rotary evaporator to provide 4,6-dimethoxy-2-methyl-nicotinamide (2.4 g, 52% ) as a light yellow solid. A solution of 4-hydroxy-3,5-dimethylbenzonitrile (2.00 g, 13.59 mmol) in DMF (20 ml) was mixed at room temperature with sodium hydride (0.706 g, 17.6 mmol) and stirred for 0.5 h. Benzyl bromide (1.82 ml, 13.59 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by adding water (200 ml), extracted with EtOAc (3x100 ml) and concentrated. The residue was purified by column chromatography to provide 4-benzyloxy-3,5-dimethylbenzonitrile (3.25 g, 100%) as a white solid. To a solution of 4,6-dimethoxy-2-methyl-nicotinamide (1 g, 5.1 mmol) in THF (120 ml) at -20 ° C was added n-BuLi (9.6 ml, 15.3 mmol) . The reaction was stirred at -20-0 ° C for 2.5 h and then cooled to -78 ° C. 4-Benzyloxy3,5-dimethylbenzonitrile (1.21 g, 5.1 mmol) was added, the cooling bath was removed, and the reaction was allowed to warm gradually to room temperature. After stirring at room temperature for 20 h, the reaction was quenched by adding water (100 ml), extracted with dichloromethane (3x100 ml) and concentrated using a rotary evaporator. The residue was further purified on a column (SiO2, hexanes / EtOAc / MeOH = 3: 2: 1) to provide 7- (4-benzyloxy-3,5-dimethyl-phenyl) -2,4-dimethoxy- [1,6 ] naphthyridine-5-ylamine (0.4 g, 19%) and 7- (4-benzyloxy-3,5-dimethyl-phenyl) -2,4-dimethoxy-6H- [1,6] naphthyridine-5-one (0 , 34 g, 16%). A solution of 7- (4-benzyloxy-3,5-dimethyl-phenyl) -2,4-dimethoxy-6H- [1,6] naphthyridine-5-one (0.34 g, 0.82 mmol) in DMF was mixed (100 ml) and MeOH (100 ml) was mixed with palladium / carbon (0.1 g) and subjected to hydrogenation (50 psi) for 2 h. The mixture was filtered through a bed of Celite. The filtrate was concentrated under high vacuum to provide 7- (4-hydroxy-3,5-dimethyl-phenyl) -2,4-dimethoxy-6H [1,6] naphthyridine-5-one (0.23 g, 88% ). A solution of 7- (4-hydroxy-3,5-dimethyl-phenyl) -2,4-dimethoxy-6H [1,6] naphthyridine-5-one (0.23 g, 0.7 mmol) was mixed in MeOH (20 ml) and DCM (20 ml) was mixed with HCl in ether (7 ml, 7 mmol) and stirred for 0.5 h. The reaction was concentrated using a rotary evaporator to obtain a solid residue. The solid was rinsed with DCM, collected by filtration, washed with DCM to provide the HCl salt of 7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-1,6-naphthyridine-5 (6H ) -one (0.15 g, 59%) as a light yellow solid. Selected data: MS (ES) m / z: 327.06; m.p. > 324 ° C in decomposition (HCl salt).

Example 7

2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4- [2- (tert-butyldimethylsilanoxy) ethoxy] 3,5-dimethylbenzaldehyde (0.856 g, 2.78 was stirred mmol) in N, N-dimethylformamide (20 ml) at 70 ° C for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70 ° C for 16 h. The reaction mixture was poured on ice and extracted with ethyl acetate. The organic phase was washed with water, brine and dried over anhydrous Na2SO4. Solvent removal gave the crude product that was purified by column chromatography to give 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (444 mg , 39%) as a white solid. Selected data: 229-231 ° C.

Alternatively, 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4- (3H) -one can be synthesized by the following method. It was placed in a 2 l dry round bottom flask with a 3,5-dimethyl-4-hydroxybenzaldehyde reflux condenser and magnetic stirrer (26.9 g, 0.179 mol) in ethanol (350 ml). 2 Chloroethanol (87.6 g, 1.074 mol) and K2CO3 (99 g, 0.716 mol) were added and the reaction mixture was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate and the organic phase was washed with water, brine and dried over Na2SO4. After removal of the solvent gave 45 g of crude product. The crude product was purified by column chromatography (230-400 mesh silica gel; 50% ethyl acetate in hexane as eluent) to give 33.3 g (95%) of product. To a solution of 2-amino-4,6-dimethoxybenzamide (33.45 g, 0.173 mol) and 4- (2-hydroxyethoxy) -3,5-dimethylbenzaldehyde (33.3 g, 0.173 mol) in N, N-dimethylacetamide ( 300 ml), NaHSO3 (33.3 g, 0.187 mol) and p-TSA (3.2 g, 17.1 mmol) were added and the reaction mixture was heated at 150 ° C for 14 h. The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was diluted with water and stirred for 30 min. at room temperature. The separated solids were filtered and dried to give the crude product. The crude product was purified by column chromatography (230-400 mesh silica gel: 5% methanol in CH2Cl2 as eluent) to give 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5 , 7-dimethoxyquinazolin-4 (3H) -one (33 g, 52%).

Example 8 (reference example)

3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one

Compound 3- [4- (2-Chloro-ethoxy) -3,5-dimethyl-phenyl] -6,8-dimethoxy-isochromen-1-one (298 mg, 0.767 mmol) was dissolved in DMSO (5 ml) and N-methylpiperazine (388 mg, 3.83 mmol) and Et3N (392 mg, 3.83 mmol) were added. The reaction mixture was heated at 110 ° C for 16 h before cooling to room temperature. Water was added and the mixture was extracted with ethyl acetate. The solvent was evaporated in vacuo to leave a residue that was purified by column chromatography. The yield was 60 mg (17%). The compound 3- [3,5-dimethyl4- (2- (4-methylpiperazin-1-yl-ethoxy) -phenyl) -6,8-dimethoxy-isochromen-1-one (60 mg, 0.13 mmol) was combined ) and NH3 (2.0 M solution in ethanol, 20 ml) in a steel pump and heated at 130 ° C for 16 h. The solvent was removed and the crude compound was purified by column chromatography. The compound was then converted into the 3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyisoquinolin-1 (2H) hydrochloride salt - one (40 mg, 62%), an off-white solid. Selected data: MS (ES) m / z: 452.1; m.p. 195-198 ° C (HCl salt).

Example 9

2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

2- (4-Hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4- (3H) -one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4-hydroxy-3-methoxybenzaldehyde, using the method described for 5,7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (4-Hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (90 mg, 36%) was isolated as a white solid. Selected data: MS (m / z): 329.06; m.p. 294-296 ° C.

Example 10

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

10 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one was synthesized from 2-amino-4,6-dimethoxybenzamide and 4- [bis- (2 -hydroxy-ethyl) -amino] -benzaldehyde, using the method described for 5,7-dimethoxy-2 (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxy-quinazolin-4 (3H) -one (120 mg, 41%) was isolated as a yellow solid. Selected data: MS (m / z): 386.15; m.p. 249-251 ° C:

Example 11

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one was synthesized from 2-amino-4,5-dimethoxybenzamide and 4- (N, N -bis (2-hydroxyethyl) amino) benzaldehyde, using the method described for 5,7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one (72 mg, 24%) was isolated

20 as a yellow solid. Selected data: MS (m / z): 386.15; m.p. 268-270 ° C.

Example 12

2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one

2- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one was synthesized from 2-amino-4,5

Dimethoxybenzamide and 2,3-dihydro-benzo [1,4] dioxin-6-carbaldehyde, using the method described for 5,7-dimethoxy-2 (pyridin-2-yl) quinazolin-4 (3H) -one. 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxy-quinazolin-4 (3H) -one (180 mg, 69%) was isolated as a solid of light yellow color Selected data: MS (m / z): 341.03; m.p. 316.4-318.2 ° C.

Example 13

2- (4 - ((4-ethylpiperazin-1yl) methyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

To a solution of 4-bromoethyl-benzoic acid ethyl ester (4.0 g, 16.46 mmol) in THF (30 ml), Netylpiperazine (3.76 g, 32.92 mmol) was added and the mixture was stirred reaction mixture for 16 h at room temperature. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The combined organic phases were washed with water, brine and dried over Na2SO4. The solvent was removed to give 4.61 g of 4- (4-ethylpiperazin-1-ylmethyl) -benzoic acid ethyl ester (100% yield). LAH (0.792 g, 20.86 mmol) was taken to a 3-neck dry flask and THF (60 ml) was added with cooling. A solution of 4- (4-ethylpiperazin-1-ylmethyl) -benzoic acid (4.61 g, 16.69 mmol) in THF (10 ml) was slowly added with cooling. After the addition was completed, the reaction mixture was refluxed for 2 h. The reaction mixture was cooled to 0 ° C, 10% NaOH solution was added and then water was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, brine and dried over Na2SO4. The solvent was removed to give 2.78 g of crude (4- (4-ethylpiperazin-1-ylmethyl) phenyl) methanol in a yield of 78%. To an 3-mouth flask containing anhydrous CH2Cl2 (100 ml) cooled to -78 ° C was added oxalyl chloride (1.8 g, 14.25 mmol) and DMSO (1.85 g, 23.76 mmol) and added Stir the mixture for 15 min. at -78 ° C. The solution of (4- (4-ethylpiperazin-1-ylmethyl) phenyl) -methanol (2.78 g, 11.88 mmol) in CH2Cl2 (10 mL) was added at -78 ° C and stirred at -78 ° C for 1 h . Then Et3N (4.8 g, 47.52 mmol) was added at -78 ° C. The reaction mixture was allowed to reach room temperature. Water was added and the organic phase was separated. The aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, brine and dried over Na2SO4. Then, the solvent was removed to give crude 4- (4-ethylpiperazin-1-ylmethyl) benzaldehyde (2.5 g, 91%).

To a solution of 2-amino-4,8-dimethoxy-benzamide (150 mg, 0.76 mmol) and 4- (4-ethylpiperazin-1-ylmethyl) benzaldehyde (177 mg, 0.76 mmol) in N, N -dimethylacetamide (10 ml), NaHSO3 (150 mg, 0.84 mmol) and p-TSA (319 mg, 1.68 mmol) were added and the reaction mixture was heated at 150 ° C for 5 h. The reaction mixture was cooled to room temperature, water was added and the mixture was neutralized with NaHCO3. The solvent was removed under reduced pressure to give the crude product, which was purified by column chromatography to give 2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxy-quinazolin-4 ( 3H) -one (87 mg, 27%), which was converted into the hydrochloride salt. Selected data: MS (ES) m / z: 409.11; m.p. 278-280 ° C (in decomposition).

Example 14

2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrido [2,3-d] pyrimidin-4 (3H) -one

To a solution of 2-amino-4,6-dimethoxy-nicotinamide (1.07 g, 5.42 mmol) and 4- [2- (tert-butyldimethylsilanoxy) ethoxy] -3,5-dimethylbenzaldehyde (1.67 g, 5 , 42 mmol) in N, N-dimethylacetamide (25 ml), NaHSO3 (1.06 g, 5.97 mmol) and p-TSA (1.14 g, 5.97 mmol) were added and the mixture was heated reaction at 150 ° C for 16 h, cooled to room temperature and poured into water. The solid was collected to give 3.25 g of crude product. To a solution of the crude product (3.25 g, 6.70 mmol) in THF (50 ml), TBAF (3.6 g, 13.4 mmol) was added at 0 ° C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, brine and dried over Na2SO4. The solvent was removed, and the crude product was purified by column chromatography (230-400 mesh silica gel; 2% methanol in CH2Cl2 as eluent) to give 2- (4- (2-hydroxyethoxy) -3, 5-dimethylphenyl) -5,7-dimethoxypyrid [2,3-d] pyrimidin-4 (3H) -one (132 mg, 6%). Selected data: MS (ES) m / z: 371.99:

m.p. 255-256 ° C.

Example 15

2- (2-Chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one

Following the method described for 5,7-dimethoxy-2- (4-methoxy-3,5-dlmethylphenyl) quinazolin-4 (3H) -one, 2- (2-chloro-6-methylpyridin-4-yl) -5 was synthesized , 7-dimethoxyquinazolin-4 (3H) -one from 2-amino-4,6-dimethoxybenzamide and 2-chloro-6-methylisonicotinoyl chloride in 75% yield as a white solid. Selected data: 1H-NMR (300 MHz, CDCl3) 8 10.95 (s, 1H), 7.90 (s, 2H), 6.74 (d, J = 2.33 Hz, 1H), 6.51 (d, J = 2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.29 (s, 3H); MS (APCI) m / z 332 [M + H] +.

Example 16

5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4- (3H) -one

To a solution of 4-methoxy-3,5-dimethylbenzoic acid (0.100 g, 0.555 mmol) in CH2Cl2 (2.77 ml) cooled to 0-5 ° C was added oxalyl chloride (67.8 µL, 0.777 mmol) followed by the dropwise addition of DMF (4.3 µL, 0.056 mmol). The mixture was stirred for 50 min., Volatile components were removed in vacuo, and the crude acid chloride was used immediately without further purification.

To a mixture of 2-amino-4,6-dimethoxybenzamide (0.0990 g, 0.566 mmol) and pyridine (44.9 µL, 0.555 mmol) in THF (2.02 mL) a solution was added dropwise of the acid chloride (crude residue described above) in THF (925 µl). After 16 h, the mixture was diluted with EtOAc (300 ml), washed with saturated aqueous NH4Cl (3x75 ml), saturated aqueous NaHCO3 (3x75 ml) and brine (75 ml). The insoluble yellow solid was isolated by filtration to provide the amide (0.150 g, 83%). A mixture of the amide (0.148 g, 0.413 mmol) and 2M NaOH (7.00 ml) was heated at 85 ° C for 19 h, cooled to 5 ° C and neutralized with 4M HCl in dioxanes. The white solid was filtered and rinsed with acetone to provide 5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) one (0.144 g, 100%). Selected data: 1H-NMR (300 MHz, CDCl3) 8 11.00 (s, 1H), 7.90 (s, 2H), 6.74 (d, J = 2.33 Hz, 1H), 6.51 (d, J = 2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H), 2.29 (s, 6H), MS (APCI) m / z 341 [M + H] +.

Example 17

2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one

To a solution of 3,5-dimethyl-4-nitrobenzoic acid (1.00 g, 5.12 mmol) in CH2Cl2 (25.6 ml) cooled to 0-5 ° C was added oxalyl chloride (0.626 ml, 7, 17 mmol) followed by the dropwise addition of DMF (39.8 µl). The mixture was stirred for 2 h, volatile components were removed in vacuo, and the crude acid chloride was used immediately without further purification. To a mixture of 2-amino-4,6-dimethoxybenzamide (0.913 g, 4.65 mmol) and pyridine (414 µL, 5.12 mmol) in THF (18.6 mL) a solution was added dropwise of the acid chloride (crude residue described above) in THF (8.53 ml). After 16 h, the mixture was diluted with EtOAc (500 ml), washed with saturated aqueous NH4Cl (3x100 ml), saturated aqueous NaHCO3 (3x100 ml) and brine (100 ml). The insoluble yellow solid was isolated by filtration to provide the amide (1.51 g, 87%). A mixture of the

amide (1.50 g, 4.03 mmol) and 2M aqueous NaOH (25.0 ml) at 85 ° C for 17 h, then THF (50 ml) was added and stirred at reflux for 25 h. Volatile components were removed in vacuo, the mixture was cooled to 5 ° C, and neutralized with 4M HCl in dioxanes. After stirring for 30 min., The white solid was filtered and lyophilized in MeCN / H2O to provide the cyclic compound (1.36 g, 95%). A mixture of the cycled compound (0.200 g, 0.563 mmol), Na2S2O4 (0.980 g, 5.63 mmol), water (5.00 ml) and MeOH (15.0 ml) was stirred at 70 ° C for 2 h. Volatile components were removed in vacuo, then diluted with EtOAc (200 ml), washed with saturated NaHCO3 (2x100 ml) and brine (75 ml). The organic phase was dried over sodium sulfate, filtered and volatile components removed in vacuo to provide 2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.062 g, 34%) as a yellow solid. Selected data: 1H-NMR (300 MHz, DMSO-d6) 8 11.45 (s, 1H), 7.78 (s, 2H), 6.66 (d, J = 2.25 Hz, 1H), 6 , 42 (d, J = 2.24 Hz, 1H), 5.26 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.14 (s, 6H) ; MS (APCI) m / z 326 [M + H] +.

Example 18

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (left)

Y

2- (4- (2-Aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (right)

A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N- (2-bromoethyl) -phthalimide (1.22 g, 4.80 mmol), K2CO3 (0.829 was heated to 80 ° C g, 6.00 mmol), Nal (3.00 g, 20.0 mmol) in DMF (40.0 ml) for 2.5 h. The reaction was cooled to room temperature, diluted with EtOAc (200 ml), washed with 1M NaOH (2x100 ml), 1M HCl (2x100 ml), brine (75 ml), dried over sodium sulfate, dried. filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (40 g, hexanes / EtOAc) to provide the expected ether (0.300 g, 23%) as a yellow solid. A mixture of the above ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol) and p-TsOH • H2O were stirred under reflux (0.0173 g, 0.0907 mmol) in DMA (11.3 ml) for 1.5 h then cooled to room temperature. The mixture was diluted with EtOAc (250 ml), washed with saturated aqueous ammonium chloride (3x75 ml) and brine (75 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (40 g, CH2Cl2 / CH3OH) to provide the expected product (0.076 g, 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2M methylamine in THF (25.0 ml) was stirred at room temperature for 17 h. Volatile components were removed in vacuo and the residue was subjected to silica gel chromatography to provide compound N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl ) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (0.0493 g, 22%) and the compound 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.0360 g, 23%) as white solids. Selected data for N1- (2- (4 (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide: 1 H-NMR (300 MHz, DMSO-d6) 8 11.80 (s, 1H), 8.51 (t, J = 5.57 Hz, 1H), 8.18 (q, J = 4.57 Hz, 1H), 7, 89 (s, 2H), 7.53-7.42 (m, 4H), 6.74 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2.29 Hz, 1H ), 3.96-3.80 (m, 8H), 3.61 (q, J = 5.73 Hz, 2H), 2.71 (d, J = 4.62 Hz, 3H), 2.32 (s, 6H): MS (APCI) m / z 531 [M + H] +. Selected data for 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one: 1 H-NMR (300 MHz, DMSO-d6) 8 7.90 (s, 2H), 6.74 (d, J = 2.31 Hz, 1H), 6.51 (d, J = 2.32 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.77 (t, J = 5.76 Hz, 2H), 2.91 (t, J = 5.75 Hz, 2H), 2.30 (s, 6H); MS (APCI) m / z 370 [M + H] +.

Example 19

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) 4-methoxybenzenesulfonamide

A mixture of 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.060 g, 0.162 mmol), 4-methoxybenzenesulfonyl chloride (0.044) was stirred. mg, 0.211 mmol) and triethylamine (29.4 µL, 0.211 mmol) in CH2Cl2 (812 µL) at room temperature for 3 h. The sample was subjected directly to silica gel chromatography to provide N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl ) -4methoxybenzenesulfonamide (0.046 g, 53%) as a white solid after lyophilization in MeCN / H2O. Selected data: 1H-NMR (300 MHz, DMSO-d6) 8 ppm 11.81 (s, 1H), 7.88 (s, 2H), 7.83-7.73 (m, 3H), 7.17 -7.07 (m, 2H), 6.73 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2.29 Hz, 1H), 3.91-3.75 ( m, 11H), 3.12 (q, J = 5.75 Hz, 2H), 2.24 (s, 6H); MS (APCI) m / z 540 [M + H] +.

Example 20

4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide

Following the method described for N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4methoxybenzenesulfonamide, the compound was prepared 4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethylphenoxy) ethyl) benzene sulfonamide from 2- ( 4- (2-Aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin4 (3H) -one in 51% yield and was isolated as a white solid after lyophilization in MeCN / H2O. Selected data: 1H-NMR (300 MHz, DMSO-d6) 8 ppm 11.8 (s, 1H), 8.1 (s, 1H), 7.9-7.6 (m, 6H), 6.75 (1H), 6.5 (1H), 3.9-3.7 (m, 8H), 3.15 (m, 2H), 2.2 (s, 6H); MS (APCI) m / z 544 [M + H] +.

Example 21

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide

A mixture of 3,5-dimethyl-4-hydroxybenzaldehyde (0.600 g, 4.00 mmol), N- (2-bromoethyl) phthalimide (1.22 g, 4.80 mmol), K2CO3 (0.829 g, 6.00 mmol), Nal (3.00 g, 20.0 mmol) in DMF (40.0 ml) at 80 ° C for 2.5 h. The reaction was cooled to room temperature, diluted with EtOAc (200 ml), washed with 1M NaOH (2x100 ml), 1M HCl (2x100 ml), brine (75 ml), dried over sodium sulfate, dried. filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (40 g, hexanes / EtOAc) to provide the expected ether (0.300 g, 23%) as a yellow solid. A mixture of the above ether (0.293 g, 0.907 mmol), 2-amino-4,6-dimethoxybenzamide (0.178 g, 0.907 mmol), NaHSO3 (94%, 0.100 g, 0.907 mmol) and p-TsOH • H2O were stirred under reflux (0.0173 g, 0.0907 mmol) in DMA (11.3 ml) for 1.5 h, then cooled to room temperature. The mixture was diluted with EtOAc (250 ml), washed with saturated aqueous ammonium chloride (3x75 ml) and brine (75 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (40 g, CH2Cl2 / CH3OH) to provide the expected product (0.075 g, 17%) as a light yellow solid. A mixture of the above compound (0.213 g, 0.426 mmol) and 2M methylamine in THF (25.0 ml) was stirred at room temperature for 17 h. Volatile components were removed in vacuo and the residue was subjected to silica gel chromatography to provide compound N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl ) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide (0.0493 g, 22%) and the compound 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.0360 g, 23%) as white solids. Selected data for N1- (2- (4 (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide: 1 H-NMR (300 MHz, DMSO-d6) 8 11.80 (s, 1H), 8.51 (t, J = 5.57 Hz, 1H), 8.18 (q, J = 4.57 Hz, 1H), 7, 89 (s, 2H), 7.53-7.42 (m, 4H), 6.74 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2.29 Hz, 1H ), 3.96-3.80 (m, 8H), 3.61 (q, J = 5.73 Hz, 2H), 2.71 (d, J = 4.62 Hz, 3H), 2.32 (s, 6H); MS (APCI) m / z 531 [M + H] +.

Example 22

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide

A mixture of 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.060 g, 0.162 mmol), 4-methoxybenzenesulfonyl chloride (0.044) was stirred. mg, 0.211 mmol) and triethylamine (29.4 µL, 0.211 mmol) in CH2Cl2 (812 µL) at room temperature for 3 h. The sample was subjected directly to silica gel chromatography to provide N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl ) -4methoxybenzenesulfonamide (0.046 g, 53%) as a white solid after lyophilization in MeCN / H2O. Selected data: 1H-NMR (300 MHz, DMSO-d6) 8 ppm 11.81 (s, 1H), 7.88 (s, 2H), 7.83-7.73 (m, 3H), 7.17 -7.07 (m, 2H), 6.73 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2.29 Hz, 1H), 3.91-3.75 ( m, 11H), 3.12 (q, J = 5.75 Hz, 2H), 2.24 (s, 6H);

10 MS (APCI) m / z 540 [M + H] +.

Example 23

4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide

Following the method described for N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4

15 methoxybenzenesulfonamide, the compound 4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethylphenoxy) ethyl) benzene- was prepared sulfonamide from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin4 (3H) -one in 51% yield and was isolated as a white solid after lyophilization in MeCN / H2O. Selected data: 1H-NMR (300 MHz, DMSO-d6) 8 ppm 11.8 (s, 1H), 8.1 (s, 1H), 7.9-7.6 (m, 6H), 6.75 (1H), 6.5 (1H), 3.9-3.7 (m, 8H), 3.15 (m, 2H), 2.2 (s, 6H); MS (APCI) m / z 544 [M + H] +.

20 Example 24

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide

Following the method described for N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4methoxybenzenesulfonamide, the compound was prepared N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2.6

Dimethylphenoxy) ethyl) methanesulfonamide from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) one in 42% yield and was isolated as a solid white after lyophilization in MeCN / H2O. Selected data: 1H-NMR (300 MHz, DMSO-d6) 8 ppm 11.82 (s, 1H), 7.90 (s, 2H), 7.33 (t, J = 5.94 Hz, 1H), 6.74 (d, J = 2.31 Hz, 1H), 6.52 (d, J = 2.30 Hz, 1H), 3.92-3.81 (m, 8H), 3.41-3 , 34 (m, 2H), 2.97 (s, 3H), 2.32 (s, 6H); MS (APCI) m / z 448 [M + H] +.

Example 25

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl propylcarbamate

A mixture of 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.070 g, 0.19 mmol) was stirred,

propyl isocyanate (0.088 ml, 0.94 mmol) and TEA (0.14 g, 1.1 mmol) in THF (4.0 ml) at 70 ° C for 16 h. Leaked

5 the mixture was washed with THF, and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 ml) and

washed with saturated aqueous sodium bicarbonate (50 ml), dried and the solvent removed under reduced pressure. Be

subjected the resulting solid to silica gel chromatography to provide 2- (4- (5,7 (5- (5.7)

dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl (0.035 g, 41%) as an off-white solid:

Selected data: 1H-NMR (300 MHz, DMSO-d6) 8 11.82 (s, 1H), 7.90 (s, 2H), 7.23 (t, J = 5.27 Hz, 1H), 6 , 74 (d, J 10 = 2.32 Hz, 1H), 6.52 (d, J = 2.31 Hz, 1H), 4.27 (t, J = 4.29 Hz, 2H), 3, 99 (t, J = 4.29 Hz, 2H), 3.89 (s, 3H), 3.84 (s,

3H), 3.02-2.86 (m, 2H), 2.29 (s, 6H), 1.50-1.30 (m, 2H), 0.84 (t, J = 7.33 Hz , 3H); MS (APCI) m / z 456 [M + H] +.

Example 26

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl-2,6-dimethyl-phenoxy) ethyl methylcarbamate

Following the method described for 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl propylcarbamate, the 2- methylcarbamate compound was prepared (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethyl-phenoxy) ethyl from 2- (4- (2-hydroxyethoxy) -3.5 -dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with a yield of 11% and was isolated as an off-white solid: 1 H-NMR (300 MHz, DMSO-d6) 8 11.82 (s, 1H), 7.90 (s, 2H), 7.08 (m, 1H), 6.74 (d, J = 2.29 Hz, 1H), 6.52 (d, J = 2.27 Hz, 1H), 4.27 (t, J = 4.55 Hz, 2H), 3.99 (t, J =

20 4.55 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 2.60 (d, J = 4.57 Hz, 3H), 2.29 (s, 6H ); MS (APCI) m / z 428 [M + H] +.

Example 27

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide

A mixture of compound 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.060 g, was stirred.

0.16 mmol), p-toluoyl chloride (0.028 ml, 0.21 mmol) and PS-DIEA (0.057 g, 0.21 mmol) in CH2Cl2 (4.0 ml) at room temperature for 16 h. The mixture was filtered, washed with CH2Cl2 and the solvent was removed under reduced pressure. The resulting residue was subjected to silica gel chromatography to provide N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) - 4-methylbenzamide (0.037 g, 51%) as an off-white solid: 1 H-NMR (300 MHz, DMSO-d6) 8 11.80-11.00 (s, 1 H), 8.69 (t, J = 5.43 Hz, 1H), 7.88 (s, 2H), 7.79

30 (d, J = 8.19 Hz, 2H), 7.28 (d, J = 8.00 Hz, 2H), 6.73 (d, J = 2.31 Hz, 1H), 6.51 ( d, J = 2.31 Hz, 1H), 3.94 (t, J = 5.59 Hz, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.72- 3.60 (m, 2H), 2.36 (s, 3H), 2.27 (s, 6H); MS (APCI) m / z 488 [M + H] +.

Example 28

2- (4- (5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate

A mixture of 4- (6,8-dimethoxyisoquinolin-3-yl) -2,6-dimethylphenol (0.100 g, 0.270 mmol), cyclohexyl isocyanate (172 µL, 1.35 mmol) and Et3N ( 263 µL, 1.89 mmol) in THF (1.00 ml) for 4 h, then diluted with EtOAc (200 ml) and washed with saturated aqueous ammonium chloride (3 x 75 ml) and brine (75 ml ). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography (12 g, CH2Cl2 / CH3OH) and the product was freeze dried in MeCN / H2O to provide 2- (4- (5,7-dimethoxy-4-oxo-3 cyclohexylcarbamate) , 4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl (0.0981 g, 73%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) 8 11.82 (s, 1H), 7.90 (s, 2H), 7.24-7.05 (m, 1H), 6.73 (d, J = 2.30 Hz, 1H), 6.52 (d, J = 2.31 Hz, 1H), 4.30-4.22 (m, 1H), 4.03-3.95 (m, 1H) , 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 6H), 1.82-1.46 (m, 5H), 1.18 (m, 5H); MS (APCI) m / z 496 [M + H] +.

Reference Example A

4- (2- (4- (6,8-dimethoxyisoquinolin-3-yl) -2,6-dimethylphenoxy) ethyl) morpholine

To a solution of 4- (6,8-dimethoxyisoquinolin-3-yl) -2,6-dimethylphenol (0.309 g, 1.0 mol) in anhydrous THF (20 ml), triphenylphosphene (0.52 g, was added) 2.0 mmol), 4- (2-hydroxyethyl) morpholine (0.262 g, 2.0 mmol) and N, N-diisopropylethylamine (0.387 g, 3.0 mmol). To this solution with stirring was added diethyl azodicarboxylate (0.348 g, 2.0 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen, then diluted with ethyl acetate (100 ml). The organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The crude material was purified by column chromatography to give 3- [3,5-dimethyl-4- (2-morpholin-4-ylethoxy) phenyl] -6,8-dimethoxyisoquinoline (0.54 g) as a white solid.

To a solution of the above compound (0.54 g, impure) in 1: 1 ether-CH2Cl2 (10 ml), 1.0 M solution of hydrogen chloride in ether (2 ml) was added and the mixture was stirred reaction at room temperature for 30 min. The solvent was removed under reduced pressure. The residue was triturated with 10% methanol in ether to give 4- (2- (4- (6,8-dimethoxyisoquinolin-3-yl) -2,6-dimethylphenoxy) ethyl) morpholine (0.323 g, 70% over two stages) as a yellow solid. Selected data: MS (ES) m / z: 423.1; m.p. 239-240 ° C (HCl salt).

Example 29

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide

Following the methodology described for reference example A, the title compound was prepared from 2 (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with a yield of 41% and was isolated as an off-white solid: MS (APCI) m / z 510 [M + H] +.

Example 30

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide

Following the methodology described for reference example A, the title compound was prepared from 2 (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with 50% yield and was isolated as an off-white solid: MS (APCI) m / z 524 [M + H] +.

Reference Example B

5,7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one

A solution of 2-amino-4,6-dimethoxybenzamide (0.15 g, 0.764 mmol) in N, N-dimethylacetamide (5 ml) is given

10 added 2-pyridinecarboxaldehyde (0.082 g, 0.764 mmol), sodium hydrogen sulphide (58.5%, 0.15 g, 0.84 mmol) and p-toluenesulfonic acid (15 mg, 0.0764 mmol). The reaction mixture was stirred at 150 ° C overnight. The mixture was cooled to room temperature. Water (40 ml) was added and the reaction mixture was extracted with dichloromethane (2x50 ml). The combined organic phases were washed with water and dried over anhydrous Na2SO4. The solvent was removed and the crude compound was purified by column chromatography (230-400 mesh silica gel;

15% methanol in CH2Cl2 as eluent) to give 5,7-dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one (0.077 g, 36%) as a white solid. 5,7-Dimethoxy-2- (pyridin-2-yl) quinazolin-4 (3H) -one was converted into the corresponding hydrochloride. Selected data: MS (m / z): 284.0; m.p. 215-217 ° C (hydrochloride).

Reference Example C

20 5,7-dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) -one

5,7-Dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) -one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3-pyridinecarboxaldehyde, using the method described for reference example B 5,7-Dimethoxy-2- (pyridin-3-yl) quinazolin-4 (3H) -one (105 mg, 48%) was isolated as a white solid. Selected data: MS (m / z): 284.0; m.p. 257-259 ° C (hydrochloride).

25 Example 31

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzamide

Following the methodology described for reference example C, the title compound was prepared from 2 (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with a yield of 46% and was isolated as a white solid: MS (APCI) m / z 526 [M + Na] +.

Example 32

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethylacetamide

Following the methodology described for example 27, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with a yield of 40% and was isolated as a white solid: MS (APCI) m / z 412 [M + H] +.

Example 33

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide

Following the methodology described for example 27, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one in a yield 66% and was isolated as a white solid: MS (APCI) m / z 474 [M + H] +.

Example 34

15 N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) isobutyramide

Following the methodology described for example 27, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with a yield of 59% and was isolated as a white solid: MS (APCI) m / z 440 [M + H] +.

Example 35

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-methylurea

A mixture of compound 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (0.10 g, 0.27 mmol), isocyanate was stirred. methyl (0.020 g, 0.35 mmol) and Et3N (0.034 g, 0.35 mmol) in THF (4.0 ml) at room temperature for 16 hours. The mixture was filtered, washed with CH2Cl2 and the solvent was removed under reduced pressure. Be

The resulting residue was chromatographed on silica gel to provide the title compound (0.082 g, 71%) as a white solid: MS (APCI) m / z 449 [M + Na] +.

Example 36

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea

Following the methodology described for example 35, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with a yield of 57% and was isolated as a white solid: MS (APCI) m / z 541 [M + Na] +.

Example 37

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea

Following the methodology described for example 35, the title compound was prepared from 2- (4- (210 aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with a yield 59% and was isolated as a light yellow solid: MS (APCI) m / z 489 [M + H] +.

Example 38

3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethylurea

15 Following the methodology described for Example 35, the title compound was prepared from 2- (4- (2-aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one with a yield 59% and was isolated as a white solid: MS (APCI) m / z 441 [M + H] +.

Example 39 (reference example)

1,1-6,8-dimethoxy-3- (4-hydroxy-3,5-dimethylphenyl) -2H-1,2-benzothiazine dioxide

To a 3-mouth round bottom flask, 3,5-dimethoxytoluene (6.088 g, 40 mmol) and cyclohexane (28 ml) were added under nitrogen. Dimethyl carbonate (30.3 g, 336 mmol) was added and the reaction mixture was heated to 60 ° C. Excess chlorosulfonic acid was added over a period of 15 min. The released HCl gas was removed by inserting a tube in solid sodium hydroxide. After completion of the addition, the reaction mixture was heated to 70-72 ° C for 1 h and then cooled to room temperature. The solid was filtered off and washed with dimethyl carbonate / cyclohexane (1: 1, 20 ml). The solid was dried under vacuum to obtain pure material (6.13 g, 66%). To a mixture of sulfonic acid (product of the above, 4.65 g, 20 mmol) and triethylamine (2.03 g, 2.79 ml) in acetone (40 ml) was added 2,4,6-trichloro- 1,3,5-triazine (cyanuric chloride, 3.69 g, 20 mmol). The mixture of was heated to reflux

reaction for 20 h before cooling to room temperature. The solution was passed through a bed of Celite and evaporated in vacuo to leave a solid, which was filtered off and washed with hexane. The product and salt mixture of cyanuric hydroxide and triethylamine (7.58 g) was used for the next step without further purification.

To a 3-round round bottom flask, equipped with a condenser (cooling with dry acetone-ice), the mixture from the previous stage (7.58 g) and acetone (100 ml) was added. The reaction mixture was cooled to -78 ° C and ammonia gas was bubbled through the solution for 0.5 h. The reaction mixture was allowed to stand overnight, allowing slow evaporation of ammonia gas, followed by evaporation of solvent. Water was added and the product was extracted with DCM. The solvent was dried and evaporated to leave a mixture of solid and a dense liquid. The solid was filtered off and washed with hexane to leave pure sulfonamide (3.23 g, 70%).

To a round bottom flask was added 3,5-dimethyl-4-hydroxybenzoic acid (2.99 g, 18 mmol). Anhydrous DMF (20 ml) was added, followed by sodium hydride (1.8 g, 45 mmol). The reaction mixture was stirred at room temperature for 1 h. P-Methoxybenzyl chloride (6.20 g, 39.6 mmol) was added and the mixture was stirred at temperature

20 h). The reaction mixture was poured into water, acidified with 1 N HCl and stirred
׽ environment during the night (

for 1 h. The precipitated solid was filtered off, washed with water and hexane to obtain the pure B ring structural element (6.93 g, 95%).

The structural element of ring B (6.93 g, 17.1 mmol) was dissolved in a mixture of methanol (50 ml) and tetrahydrofuran (50 ml). Potassium hydroxide (1.25 g, 22.2 mmol) in water (20 ml) was added. The reaction mixture was refluxed at 70 ° C for 24 h. The solvent was evaporated in vacuo. Water was added and the reaction mixture was acidified with 1 N HCl (pH 4-5). The solid was filtered off, washed with water and hexane. The yield was 4.61 g (94%). The product (1,932 g, 6.75 mmol) and the sulfonamide of the above (1.04 g, 4.5 mmol) were taken to a 3-neck round bottom flask under nitrogen. Dichloromethane (100 ml) was added with stirring. To this mixture with stirring was added N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDCI. HCl, 1.36 g, 7.09 mmol), followed by N, N-dimethylaminopyridine (2.06 g , 16.9 mmol). The reaction mixture was stirred at room temperature for 24 h before washing with 1 N HCl, 2.5% NaOH and saturated sodium bicarbonate solutions. The organic phases were dried and evaporated in vacuo to leave a residue, which was purified by column chromatography on silica gel (100 g), using 20-50% ethyl acetate in hexane and 5% methanol in dichloromethane as eluents Fractions 30-66 were combined to obtain pure materials (1.35 g, 60%). The compound from the previous step (0.105 g, 0.21 mmol) was dissolved in tetrahydrofuran under nitrogen and cooled to -78 ° C. N-Butyllithium was added and the reaction mixture was allowed to warm to room temperature

14 h). The CCF showed incomplete conversion. The mixture was extinguished
׽ slowly and stirred overnight

reaction with saturated ammonium chloride solution and extracted with ethyl acetate. The solvent was evaporated in vacuo to leave a residue that was purified by column chromatography on silica gel (15 g), using 20-50% ethyl acetate in hexane as eluents. The product was not pure enough, so another column was used, using 0.5% methanol in hexane as eluent, and finally preparative TLC was used to purify the material. The compound from the previous step (0.277 g) was dissolved in trifluoroacetic acid (10 ml) under nitrogen and the reaction mixture (bath temperature of 80 ° C) was refluxed for 4 d. The solvent was evaporated in vacuo and the residue was dissolved in 0.25 N NaOH (20 ml) and acidified with acetic acid. The solid had precipitated at this point. The solid was filtered off and washed with water, hexane and dried. From a batch, 0.005 g of pure material was isolated. From another batch, 0.060 g of the compound was isolated, which was not pure enough. This compound was further purified by preparative HPLC to give pure 1,1,8-dimethoxy-3- (4-hydroxy-3,5-dimethylphenyl) -2H-1,2-benzothiazine dioxide (0.010 g). Selected data: m.p. 246.6247.4 ° C.

Example 40 (reference example)

3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxy-7- (morpholinomethyl) isoquinolin-1 (2H) -one

Methyl acetoacetate (69.67 g, 0.6 mol) in dry THF (350 ml) was cooled to -5 ° C and sodium hydride in mineral oil (24.5 g, 60%) was added at -5 to 0 ° C over 30 min. Dicetena (50.4 g) in dry THF (80 ml) was added dropwise at 5 ° C over 20 min. The resulting solution was allowed to stir for 1.0 h at -5 ° C, after which it was allowed to warm to room temperature and stir overnight. Acetic acid (35 ml) was added and the THF solvent was removed. Water (200 ml) and ethyl acetate (300 ml) were added to the residue and the pH was adjusted to 5.0 by the addition of HCl solution. The organic phase was separated and washed with brine and dried over sodium sulfate. After column purification and recrystallization, compound A (26.6 g, 24.3%) was obtained.

Sodium hydride in mineral oil (11.2 g, 0.299 mol, 60%) was added to compound A (24.8 g, 0.136 mol) in DMF (150 ml). The reaction was cooled to -30 ° C and methyl iodide (21.3 ml, 0.341 mol) was added and the reaction was maintained at room temperature overnight. Sodium iodide was filtered off and DMF was removed. The residue was mixed with water (100 ml) and extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. The crude mixture was purified by column chromatography to provide compound B (11.40 g, 39.9%). To a solution of compound B (11.4 g, 0.054 mol) in dry CCl4 (90 ml) was added N-bromosuccinimide (10.6 g, 0.0596 mol). The mixture was refluxed overnight and the CCl4 solvent was removed. Water (100 ml) was added to the residue. After stirring for a while, the solid was filtered off and washed with water, ethyl acetate (10 ml) and hexane (30 ml) to give the compound (13.1 g, 83.9%). Compound C (12.5 g, 0.043 mol), chloromethyl methyl ether (81.0 g) and anhydrous zinc chloride (7.0 g, 0.051 mol) were kept at room temperature overnight. Chloromethyl methyl ether was removed. and the residue was mixed with water and the pH was adjusted to 7.0 using sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. Compound D (7.39 g, 50.6%) was obtained after column chromatography. A solution of compound D (7.39 g, 0.022 mol), morpholine (7.62 g, 0.088 mol) and anhydrous THF (20 ml) was maintained at room temperature overnight. The solvent was evaporated. Water and ethyl acetate were added to the residue and the pH was adjusted to 9.0 with sodium bicarbonate. The organic phase was washed with brine and dried over sodium sulfate and concentrated. Compound E (5.4 g, 63.8%) was obtained after column chromatography. The hydrogenation reaction was carried out at 50 psi with compound E (5.4 g, 0.014 mol) in THF (100 ml) and triethylamine (3.9 ml) with 10% Pd / C (2.6 g ) as catalyst for 2 d. After filtration of the catalyst, the organic phase was purified by column chromatography to provide product F (3.20 g, 74.4%). Compound F was dissolved (3.20 g, 0.0103 mol) in ethanol (30 ml) and potassium hydroxide (2.31 g, 0.041 mol) in water (20 ml) was added and the reaction mixture was heated up to 100 ° C overnight. The solvent was removed, the pH was adjusted to 6.0 and the water was removed. The residue was further dried under high vacuum and the compound was extracted with ethanol to provide compound G (2.95 g, 99%). Compound G (1.80 g, 6.1 mmol) was refluxed with thionyl chloride (3 ml, 0.0411 mol) for 1 h before excess thionyl chloride was removed and the residue was dried at high empty. Anhydrous THF (20 ml) was added and ammonia gas was bubbled into the reaction mixture for 2 h. THF was removed and the pH was adjusted to 8.0-9.0. The mixture was extracted with dichloromethane and dried over sodium sulfate to give compound H (1.30 g, 72.4%).

NaH in mineral oil (1.14 g, 0.0285 mol, 60%) was added to 4-hydroxy-3,5-dimethylbenzonitrile (4.0 g, 0.027 mol) in anhydrous DMF (20 ml) followed by bromide of benzyl (3.27 ml, 0.027 mol). The reaction was maintained at room temperature overnight. The reaction mixture was poured into water and the solid was filtered off and washed with hexane to provide compound I (5.7 g, 89%). Compound I was used for the next reaction step without further purification. BuLi (1.60 M, 10.2 ml) was added dropwise to compound H (0.8 g, 2.72 mmol) in anhydrous THF (25 ml) at -10 ° C. The reaction mixture was maintained at 0 ° C for one hour before the cooling bath was removed. The reaction mixture was stirred for 45 minutes. Compound I (0.65 g, 2.72 mmol) in anhydrous THF (5 ml) was added dropwise at -10 ° C and the reaction was continued for 45 min. additional. Water (20 ml) was added. The mixture was extracted with ethyl acetate. The solvent was removed and the residue was purified by column chromatography to give compound J (0.188 g, 12.8%). Compound J (180 mg) in methanol (80 ml) was hydrogenated at 50 psi for 3 h, using 10% Pd / C as catalyst. The catalyst and solvent were removed and the residue was purified by column chromatography to provide 3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxy-7- (morpholinomethyl) isoquinolin-1 (2H) -one ( 28 mg, 18.8%) as a white solid. Selected data: MS (m / z): 424.21; m.p. 158-161 ° C.

Example 41: Quantification of ApoA-I mRNA

In this example, ApoA-I mRNA was quantified in cells in tissue culture to measure the regulation by transcriptional increase of ApoA-I when treated with a compound of the invention.

MEM, complemented! 400
׽ per well) in a 24-well plate in 52x10
׽ HepG2 cells were placed (

with 0.5% FBS (v / v), 24 h before the addition of the compound of interest. At the time of collection, spent media was removed from HepG2 cells and immediately placed on ice (for immediate use) or at -80 ° C (for future use) in ApoA-I ELISA and albumin. The remaining cells in the wells of the plate were rinsed with 200 µl of PBS. PBS was carefully removed to avoid removing any unbound cells very tightly.

Once PBS was removed, 85 µl of cell lysis solution was added to the cells in each well and incubated for 5-10 min. at room temperature, to allow complete detachment and cell lysis. Then mRNA was prepared using the "Catcher PLUS mRNA plate" of Invitrogen, according to the protocol provided. After the last wash, as much wash buffer was aspirated as possible without allowing the wells to dry. Then elution buffer (E3, 80 µl) was added to each well. The mRNA was then eluted by incubating the Catcher PLUS mRNA plate with elution buffer for 5 min. at 68 ° C and then immediately placing the plate on ice.

Then the eluted mRNA isolated in a PCR reaction at room temperature was used in real time in a single stage, using the components of the Ultra Sense kit together with primer-probe mixtures of Applied Biosystems. Real-time PCR data were analyzed, using Ct values, to determine the induction times of each unknown sample, with respect to the control (i.e., with respect to the control for each concentration in independent DMSO).

An active compound is one that causes a> 15% increase in ApoA-I mRNA at a concentration less than or equal to 100 µM.

Example No.

Compound Name Effect on ApoA-I mRNA levels

38

3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethylurea Active

37

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea Active

36

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea Active

35

1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-methylurea Active

3. 4

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) isobutyramide Active

33

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide Active

32

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) acetamide Active

31

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzamide Active

30

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide Active

29

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide Active

28

2- (4- (5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate Active

27

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide Active

26

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl methylcarbamate Active

25

2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl propylcarbamate Active

24

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide Active

2. 3

4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethylphenoxy) ethyl) benzenesulfonamide Active

22

N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide Active

twenty-one

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide Active

twenty

4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) 2,6-dimethylphenoxy) ethyl) benzenesulfonamide Active

18

2- (4- (2-Aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin4 (3H) -one Active

18

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide Active

17

2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one Active

16

5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one Active

fifteen

2- (2-Chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one Active

14

2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrid [2,3d] pyrimidin-4 (3H) -one Active

13

2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxyquinazolin4 (3H) -one Active

12

2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin4 (3H) -one Active

eleven

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) one Active

10

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) one Active

9

2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one Active

8 *

3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one Active

7

2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin4 (3H) -one Active

6 *

7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-1,6-naphthyridin-5 (6H) -one Active

5*

3- (4- (2-Hydroxy-2-methylpropoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one Active

4

2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one Active

3*

3- (4-hydroxy-3,5-dimethylphenyl) -7- (morpholinomethyl) isoquinolin-1 (2H) one Active

2*

3- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin1 (2H) -one Active

one*

3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one Active

* Reference example

Example 42: Induction of ApoA-I mRNA and protein

In this example, ApoA-I mRNA and the secreted protein from cells in tissue culture were quantified. The assay can be used to determine potency for the compounds of interest, including those of the present invention.

per well) in a 52x10
He HepG2 cells and primary human hepatocytes (BD Gentest, lot 107) (l of EMF, supplemented with 0.5% FBS (v / v), 24 hours before adding! 400 were placed
׽ 24-well plate in

compound of interest Compounds of interest were dissolved in 0.05% (v / v) DMSO. Appropriate volumes of the stock solutions of the compounds in DMSO were then added to appropriate volumes of MEM, supplemented with 0.5% (v / v) FBS, to achieve the desired concentration (eg, 1 µl of a solution

10 mother of compound in 1 ml of MEM, supplemented with 0.5% (v / v) FBS).

Just before the addition of compound to the cells, the growth media were aspirated and replaced by 300 µl of fresh MEM, supplemented with 0.5% FBS (v / v), followed by the addition of 300! l of the compound of interest in MEM, supplemented with 0.5% FBS (v / v), to achieve the desired final compound concentration in a total volume of 600 µl. The final diluent concentration (DMSO) was 0.05% (v / v).

15 Cells were incubated for the desired time. Then the cellular media were collected, as were the cells. ApoA-I mRNA was measured as described in example 39. Secreted ApoA-I was measured using an ApoA-I ELISA, as described below:

ApoA-I ELISA

In this example, the ApoA-I secreted in the tissue culture cell media was quantified to evaluate the

Induction of endogenous ApoA-I protein secretion from cells treated with various small molecule compounds, such as those of the present invention.

At the time of collection, spent media were removed from the HepG2 cell cultures or primary cell culture and stored at -80 ° C in 1.5 ml microcentrifuge tubes.

l / well of decapture antibody! 100
׽ For the human ApoA-I ELISA, an ELISA plate was coated with 1 h at room temperature.
׽ g / ml in buffer buffer for! Against diluted human ApoA-I up to ~ 2 l / well of! 200
׽ Then the plate was washed three times with wash buffer. Then the plate was blocked with 30 min. at room temperature.
׽ApoA-Ihumana blocking buffer for at least

Samples were prepared for use in generating a standard curve from spent media (MEM, supplemented with 0.5% (v / v) FBS) from HepG2 or primary cells treated with DMSO for 48 h. Be

30 prepared 2-fold serial dilutions of the media in MEM, supplemented with 0.5% (v / v) FBS. Unknown samples were also treated from cultures treated with the compounds of interest in MEM, supplemented with 0.5% FBS (v / v). The plate was washed three times with wash buffer. Samples of the standard and unknown curves (100 µl / well), in triplicate, were added to the plate and incubated for 1.5 h at room temperature.

35 The plate was washed three times with wash buffer. Detection antibody against human ApoA-I, diluted 1: 1000 in PBS, (100 µl / well) was added and the plate was incubated for 1 h at room temperature. The plate was washed three times with wash buffer.

Goat antibody conjugate anti-H and L chain of rabbit-specific peroxidase IgG, diluted 1: 2000 with PBS, (100 µl / well) was added and the plate was incubated for 40 min. at room temperature in the dark. Be

40 washed the plate six times with wash buffer.

TMB liquid substrate (100 µL / well) was added and the plate was incubated on a shaker under tin foil during development. Once a sufficient "blue" color was achieved, stop solution (50 µl / well, 1 M H2SO4) was added and mixed thoroughly in the plate shaker. Air bubbles were removed and absorbance at 450 nm was determined, using a Molecular Devices SpectraMax 190 plate reader and Softmax software for human ApoA-I ELISA.

Example No.

Compound Name EC50 Protein (! M)

twenty

4-Chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide 0.32

18

2- (4- (2-Aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one 7.22

18

N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) N2-methylphthalamide 7.29

17

2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one 7.63

16

5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one 16.46

fifteen

2- (2-Chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one 3.96

14

2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrid [2,3-d] pyrimidin-4- (3H) one 9.20

13

2-4 - ((4-ethylpiperazin-1-yl) methyl) phenyl-5,7-dimethoxyquinazolin-4 (3H) -one 13.72

12

2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one 9.07

eleven

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one 13.30

10

2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one 12.11

9

2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one 12.08

8 *

3- (3,5-dimethyl-4- (2- (4-methylpiperazin-1-yl) ethoxy) phenyl) -6,8-dimethoxyisoquinolin1 (2H) -one 2.82

7

2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one 12.16

6 *

7- (4-hydroxy-3,5-dimethylphenyl) -2,4-dimethoxy-1,6-naphthyridin-5 (6H) -one 6.52

5*

3- (4- (2-Hydroxy-2-methylpropoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) one 6.27

4

2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one 7.93

3*

3- (4-hydroxy-3,5-dimethylphenyl) -7- (morpholinomethyl) isoquinolin-1 (2H) -one 11.09

2*

3- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one 11.35

one*

3- (4-hydroxy-3,5-dimethylphenyl) -6,8-dimethoxyisoquinolin-1 (2H) -one 5.42

2- (4-Hydroxy-phenyl) -pyran [2,3-b] pyridin-4-one

179.47

* Reference example

EXAMPLE 43: Efficiency in vivo

To test whether the efficacy of the compounds of the invention observed in vitro is extended to an in vivo model, transgenic mice that carried multiple copies of the human ApoA-I gene (Bisaha et al. (1995) J.) were exposed. Biol. Chem. 34, 19979-88) or wild mice (C57BL / 6 (inventory number 000664) Jackson

Laboratory (Bar Harbor, ME)) to compounds of the invention. In transgenic mice, the exogenous human ApoA-I gene in these mice allows them to express the human ApoA-I protein under the control of their own promoter.

Male mice aged seven to eight weeks were housed, five per cage (10 ”x20” x8 ”with bed of poplar splinters) with feed for rodents in granules [Purina 5001] and water available all the time. After a period of 15 acclimatization of 1 week, the animals were individually identified by numbering them in the tail and weighed. The mice were previously drawn through the retroorbital plexus, and 100 µl of blood was collected in a 1.5 ml Eppendorf tube containing 5 µl of 0.5 mM EDTA and cooled sharply on ice. Plasma was collected after centrifuging the whole blood at 14000 rpm [TOMY NTX-150 refrigerated high speed microcentrifuge] for 10 min. at 4 ° C and frozen at -80 ° C. Mice were grouped based on whether they had an average weight of

20 25 g

One day after previous blood collection, the mice were dosed by oral probe or by administration via i.p. daily using a 11/2 ”curved disposable feeding needle, 20 gauge, (Popper & Sons): when it was b.i.d. mice were administered orally in the morning and in the afternoon (8 am and 5 pm); when it was q.d. the mice were administered by tube in the morning (8 am). Compounds were prepared every 25 days in vehicle. One day before the autopsy, the mice were weighed and fasted overnight. On the final day of dosing, mice were sacrificed after 2 h after dosing by CO2 inhalation and blood was obtained by cardiac puncture (0.7-1.0 ml). Plasma was collected and frozen at -80 ° C. Samples were tested for ApoA-I by ELISA, and C-HDL by HPLC (Polaris 200 instrument with a Varian Prostar 410 auto-injector on a Amersham Superose 6 10/30 column). During necropsy, the liver and enterocytes were collected from the duodenum and jejunum of the small intestine, cleaned with cold PBS and

frozen at -80 ° C for further analysis of mRNA and compound levels by Q-PCR.

Experiment A. 2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (10, 30 and 60 mg / kg body weight, mpk) was administered. bid to hApoA-I transgenic mice daily for seven days by oral probe in 1% DMSO, 2.5% Tween-80, 10% PEG-300, c.s. in water Plasma was tested for

5 determine ApoA-I (figure 1) and HDL cholesterol (figure 2).

Experiment B. 2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (10, 30 and 60 mg / kg body weight) b.i.d. to wild C57BL / 6 mice daily for three days by route administration

i.p. in 1% DMSO, 2.5% Tween-80, 10% PEG-300, c.s. in water Plasma was tested for ApoA-I (Figure 3) and HDL cholesterol (Figure 4).

Experiment C. 2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one (30 mg / kg body weight) b.i.d. to hApoA-I transgenic mice daily for seven days by oral probe in 1% DMSO, 2.5% Tween-80, 10% PEG-300, c.s. in water Plasma was tested for ApoA-I and tissues were tested for mRNA (Figure 5).

These results indicate that the compounds of the invention are useful for increasing the transcription of ApoAI in

15 live, and raise plasma ApoA-I levels and circulating levels of C-HDL in wild and transgenic hApoA-I mice. These results demonstrate that the compounds of the invention activate the human ApoA-I transgene in mice, leading to an increase in circulating ApoA-I.

All the bibliography referred to in this document is incorporated as a reference in its entirety. Other embodiments of the invention will be apparent to those skilled in the art taking into account

20 the descriptive report and practice of the invention disclosed herein. It is intended that the specification and examples be considered by way of example only, the true scope and spirit of the invention being indicated by the following claims.

Claims (16)

1. Compound of formula II for use to increase the expression of ApoA-I in a mammal: Formula II 5 in which: X is N; R1 and R3 are each independently selected from alkoxy and hydrogen; R2 is selected from alkoxy, alkyl and hydrogen; R6 and R8 are each independently selected from alkyl, alkoxy, chloride and hydrogen; R4 and R5 are hydrogen; R7 is selected from amino, hydroxyl, alkoxy and alkyl substituted with a heterocyclyl, or two adjacent substituents selected from R6, R7 and R8 are connected to form a heterocyclyl; each W is independently selected from C and N; 15 p is 1, with the exception that when W is N, then p is 0; in which the groups "alkyl", "alkenyl", "alkynyl", "alkoxy", "amino" and "amide" may be substituted with or interrupted by or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl , heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulphide, sulfinyl, Sulfonyl, sulfonic acid, sulfonamide, thioketone, ureido and N; with the proviso that if R2 is selected from alkoxy or hydrogen, then at least one of R1 and R3 is alkoxy; with the proviso that if R7 is selected from hydroxyl or alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy and chloride; With the proviso that if for W- (R7) p, W is N and p is 0, then at least one of R6 and R8 is chloride; and pharmaceutically acceptable salts and hydrates thereof. 2. A compound for use according to claim 1, wherein at least one of R6 and R8 is selected from alkyl, alkoxy and chloride. 3. Compound for use according to claim 1, wherein R6 and R8 are each hydrogen and W- (R7) p is 30 C- (R7) 1.

Four.

Compound for use according to claim 1 or claim 2, wherein neither R6 nor R8 is hydrogen.

5.

Compound for use according to any one of claims 1, 2 and 4, wherein R1 and R3 are alkoxy; R6 and R8 are alkyl; Y

R7 is alkoxy substituted with a hydroxyl.

6.

Compound for use according to claim 1, wherein R7 is selected from hydroxyl, amino and alkoxy.

7.

Compound for use according to any one of claims 1, 2, 4, 5 and 6, wherein the compound of formula II is 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5.7 -dimethoxyquinazolin-4 (3H) -one, or a pharmaceutically acceptable salt or hydrate thereof.

8.

Compound for use to increase ApoA-1 in a mammal, wherein the compound is selected from: 2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one; 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one; 2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrid [2,3-d] pyrimidin-4 (3H) -one; 2- (2-Chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one; 5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one; 2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide; 2- (4- (2-Aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide; 4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide; 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl propylcarbamate; 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl methylcarbamate; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide; 2- (4- (5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) acetamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) isobutyramide; 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-methylurea; 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea; 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea; and 3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethylurea,

or a pharmaceutically acceptable salt or hydrate thereof.

9.

Compound for use according to any one of claims 1-8, wherein a therapeutically effective amount of the compound of formula II is administered with a pharmaceutically acceptable carrier.

in a pharmaceutically acceptable composition.

10.

Compound for use according to any one of claims 1-8, further comprising treating or preventing a cardiovascular disorder, related to cholesterol or lipids.

eleven.

Compound of formula II:

5 Formula II in which: X is N; R1 and R3 are each independently selected from alkoxy and hydrogen; R 2 is selected from alkoxy, alkyl and hydrogen; R6 and R8 are each independently selected from alkyl, alkoxy, chloride and hydrogen; R4 and R5 are hydrogen; R7 is selected from amino, hydroxyl, alkoxy and alkyl substituted with a heterocyclyl; or 15 two adjacent substituents selected from R6, R7 and R8 are connected to form a heterocyclyl; each W is independently selected from C and N; p is 1, with the exception that when W is N, then p is 0; with the proviso that if R2 is selected from alkoxy or hydrogen, then at least one of R1 and R3 is alkoxy; With the proviso that if R7 is selected from hydroxyl or alkoxy, then at least one of R6 and R8 is independently selected from alkyl, alkoxy and chloride; with the proviso that if for W- (R7) p, W is N and p is 0, then at least one of R6 and R8 is chloride; and pharmaceutically acceptable salts and hydrates thereof. 12. Compound according to claim 11, wherein the compound is 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,725 dimethoxyquinazolin-4 (3H) -one or a pharmaceutically acceptable salt or hydrate of the same. 13. Compound selected from: 2- (4-hydroxy-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4- (2-hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4-hydroxy-3-methoxyphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4- (bis (2-hydroxyethyl) amino) phenyl) -6,7-dimethoxyquinazolin-4 (3H) -one; 2- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -6,7-dimethoxyquinazolin-4 (3H) -one; 2- (4 - ((4-ethylpiperazin-1-yl) methyl) phenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; 2- (4- (2-Hydroxyethoxy) -3,5-dimethylphenyl) -5,7-dimethoxypyrid [2,3-d] pyrimidin-4 (3H) -one; 2- (2-Chloro-6-methylpyridin-4-yl) -5,7-dimethoxyquinazolin-4 (3H) -one; 5,7-dimethoxy-2- (4-methoxy-3,5-dimethylphenyl) quinazolin-4 (3H) -one; 2- (4-amino-3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; N1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -N2-methylphthalamide; 2- (4- (2-Aminoethoxy) -3,5-dimethylphenyl) -5,7-dimethoxyquinazolin-4 (3H) -one; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzenesulfonamide; 4-chloro-N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) methanesulfonamide; 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl propylcarbamate; 2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethyl-phenoxy) ethyl methylcarbamate; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzamide; 2- (4- (5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl cyclohexylcarbamate; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzenesulfonamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methylbenzenesulfonamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -4-methoxybenzamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) acetamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) benzamide; N- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) isobutyramide; 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-methylurea; 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3- (4-methoxyphenyl) urea; 1- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -3-phenylurea; and 3- (2- (4- (5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl) -2,6-dimethylphenoxy) ethyl) -1,1-dimethylurea; and pharmaceutically acceptable salts and hydrates thereof.

14.

Pharmaceutical composition comprising a compound according to any one of claims 11 to 13 and a pharmaceutically acceptable carrier.

fifteen.

Compound according to any one of claims 11, 12 or 13 for use to treat cardiovascular disorders, related to cholesterol or lipids.

16.

Compound according to any one of claims 11, 12 or 13 for use to increase the expression of ApoA-I in a mammal.